Mitotic G1-G1/S phase involves G1 phase of the mitotic interphase and G1/S transition, when a cell commits to DNA replication and divison genetic and cellular material to two daughter cells.
During early G1, cells can enter a quiescent G0 state. In quiescent cells, the evolutionarily conserved DREAM complex, consisting of the pocket protein family member p130 (RBL2), bound to E2F4 or E2F5, and the MuvB complex, represses transcription of cell cycle genes (reviewed by Sadasivam and DeCaprio 2013).<p>During early G1 phase in actively cycling cells, transcription of cell cycle genes is repressed by another pocket protein family member, p107 (RBL1), which forms a complex with E2F4 (Ferreira et al. 1998, Cobrinik 2005). RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, is the third member of the pocket protein family. RB1 binds to E2F transcription factors E2F1, E2F2 and E2F3 and inhibits their transcriptional activity, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1-3. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1-3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997). CDK2, in complex with cyclin E, contributes to RB1 inactivation and also activates proteins needed for the initiation of DNA replication (Zhang 2007). Expression of D type cyclins is regulated by extracellular mitogens (Cheng et al. 1998, Depoortere et al. 1998). Catalytic activities of CDK4/6 and CDK2 are controlled by CDK inhibitors of the INK4 family (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995) and the Cip/Kip family, respectively.
View original pathway at:Reactome.</div>
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Goel RK, Lukong KE.; ''Tracing the footprints of the breast cancer oncogene BRK - Past till present.''; PubMedEurope PMCScholia
Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y, Sharrocks AD, Peters G, Hara E.; ''Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence.''; PubMedEurope PMCScholia
Remus D, Beuron F, Tolun G, Griffith JD, Morris EP, Diffley JF.; ''Concerted loading of Mcm2-7 double hexamers around DNA during DNA replication origin licensing.''; PubMedEurope PMCScholia
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Gao Y, Cimica V, Reich NC.; ''Suppressor of cytokine signaling 3 inhibits breast tumor kinase activation of STAT3.''; PubMedEurope PMCScholia
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Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G.; ''DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation.''; PubMedEurope PMCScholia
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Fan G, Lin G, Lucito R, Tonks NK.; ''Protein-tyrosine phosphatase 1B antagonized signaling by insulin-like growth factor-1 receptor and kinase BRK/PTK6 in ovarian cancer cells.''; PubMedEurope PMCScholia
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Sgouras DN, Athanasiou MA, Beal GJ, Fisher RJ, Blair DG, Mavrothalassitis GJ.; ''ERF: an ETS domain protein with strong transcriptional repressor activity, can suppress ets-associated tumorigenesis and is regulated by phosphorylation during cell cycle and mitogenic stimulation.''; PubMedEurope PMCScholia
Oncogene-induced senescence is triggered by high level of RAS/RAF/MAPK signaling that can be caused, for example, by oncogenic mutations in RAS or RAF proteins, or by oncogenic mutations in growth factor receptors, such as EGFR, that act upstream of RAS/RAF/MAPK cascade. Oncogene-induced senescence can also be triggered by high transcriptional activity of E2F1, E2F2 or E2F3 which can be caused, for example, by the loss-of-function of RB1 tumor suppressor.
Oncogenic signals trigger transcription of CDKN2A locus tumor suppressor genes: p16-INK4A and p14-ARF. p16-INK4A and p14-ARF share exons 2 and 3, but are expressed from different promoters and use different reading frames (Quelle et al. 1995). Therefore, while their mRNAs are homologous and are both translationally inhibited by miR-24 microRNA (Lal et al. 2008, To et al. 2012), they share no similarity at the amino acid sequence level and perform distinct functions in the cell. p16-INK4A acts as the inhibitor of cyclin-dependent kinases CDK4 and CDK6 which phosphorylate and inhibit RB1 protein thereby promoting G1 to S transition and cell cycle progression (Serrano et al. 1993). Increased p16-INK4A level leads to hypophosphorylation of RB1, allowing RB1 to inhibit transcription of E2F1, E2F2 and E2F3-target genes that are needed for cell cycle progression, which results in cell cycle arrest in G1 phase. p14-ARF binds and destabilizes MDM2 ubiquitin ligase (Zhang et al. 1998), responsible for ubiquitination and degradation of TP53 (p53) tumor suppressor protein (Wu et al. 1993, Fuchs et al. 1998, Fang et al. 2000). Therefore, increased p14-ARF level leads to increased level of TP53 and increased expression of TP53 target genes, such as p21, which triggers p53-mediated cell cycle arrest and, depending on other factors, may also lead to p53-mediated apoptosis. CDKN2B locus, which encodes an inhibitor of CDK4 and CDK6, p15-INK4B, is located in the vicinity of CDKN2A locus, at the chromosome band 9p21. p15-INK4B, together with p16-INK4A, contributes to senescence of human T-lymphocytes (Erickson et al. 1998) and mouse fibroblasts (Malumbres et al. 2000). SMAD3, activated by TGF-beta-1 signaling, controls senescence in the mouse multistage carcinogenesis model through regulation of MYC and p15-INK4B gene expression (Vijayachandra et al. 2003). TGF-beta-induced p15-INK4B expression is also important for the senescence of hepatocellular carcinoma cell lines (Senturk et al. 2010).
MAP kinases MAPK1 (ERK2) and MAPK3 (ERK1), which are activated by RAS signaling, phosphorylate ETS1 and ETS2 transcription factors in the nucleus (Yang et al. 1996, Seidel et al. 2002, Foulds et al. 2004, Nelson et al. 2010). Phosphorylated ETS1 and ETS2 are able to bind RAS response elements (RREs) in the CDKN2A locus and stimulate p16-INK4A transcription (Ohtani et al. 2004). At the same time, activated ERKs (MAPK1 i.e. ERK2 and MAPK3 i.e. ERK1) phosphorylate ERF, the repressor of ETS2 transcription, which leads to translocation of ERF to the cytosol and increased transcription of ETS2 (Sgouras et al. 1995, Le Gallic et al. 2004). ETS2 can be sequestered and inhibited by binding to ID1, resulting in inhibition of p16-INK4A transcription (Ohtani et al. 2004).
Transcription of p14-ARF is stimulated by binding of E2F transcription factors (E2F1, E2F2 or E2F3) in complex with SP1 to p14-ARF promoter (Parisi et al. 2002).
Oncogenic RAS signaling affects mitochondrial metabolism through an unknown mechanism, leading to increased generation of reactive oxygen species (ROS), which triggers oxidative stress induced senescence pathway. In addition, increased rate of cell division that is one of the consequences of oncogenic signaling, leads to telomere shortening which acts as another senescence trigger.
Oxidative stress, caused by increased concentration of reactive oxygen species (ROS) in the cell, can happen as a consequence of mitochondrial dysfunction induced by the oncogenic RAS (Moiseeva et al. 2009) or independent of oncogenic signaling. Prolonged exposure to interferon-beta (IFNB, IFN-beta) also results in ROS increase (Moiseeva et al. 2006). ROS oxidize thioredoxin (TXN), which causes TXN to dissociate from the N-terminus of MAP3K5 (ASK1), enabling MAP3K5 to become catalytically active (Saitoh et al. 1998). ROS also stimulate expression of Ste20 family kinases MINK1 (MINK) and TNIK through an unknown mechanism, and MINK1 and TNIK positively regulate MAP3K5 activation (Nicke et al. 2005).
MAP3K5 phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997, Takekawa et al. 2005), which act as p38 MAPK kinases, as well as MAP2K4 (SEK1) (Ichijo et al. 1997, Matsuura et al. 2002), which, together with MAP2K7 (MKK7), acts as a JNK kinase.
MKK3 and MKK6 phosphorylate and activate p38 MAPK alpha (MAPK14) and beta (MAPK11) (Raingeaud et al. 1996), enabling p38 MAPKs to phosphorylate and activate MAPKAPK2 (MK2) and MAPKAPK3 (MK3) (Ben-Levy et al. 1995, Clifton et al. 1996, McLaughlin et al. 1996, Sithanandam et al. 1996, Meng et al. 2002, Lukas et al. 2004, White et al. 2007), as well as MAPKAPK5 (PRAK) (New et al. 1998 and 2003, Sun et al. 2007).
Phosphorylation of JNKs (MAPK8, MAPK9 and MAPK10) by MAP3K5-activated MAP2K4 (Deacon and Blank 1997, Fleming et al. 2000) allows JNKs to migrate to the nucleus (Mizukami et al. 1997) where they phosphorylate JUN. Phosphorylated JUN binds FOS phosphorylated by ERK1 or ERK2, downstream of activated RAS (Okazaki and Sagata 1995, Murphy et al. 2002), forming the activated protein 1 (AP-1) complex (FOS:JUN heterodimer) (Glover and Harrison 1995, Ainbinder et al. 1997).
Activation of p38 MAPKs and JNKs downstream of MAP3K5 (ASK1) ultimately converges on transcriptional regulation of CDKN2A locus. In dividing cells, nucleosomes bound to the CDKN2A locus are trimethylated on lysine residue 28 of histone H3 (HIST1H3A) by the Polycomb repressor complex 2 (PRC2), creating the H3K27Me3 (Me3K-28-HIST1H3A) mark (Bracken et al. 2007, Kotake et al. 2007). The expression of Polycomb constituents of PRC2 (Kuzmichev et al. 2002) - EZH2, EED and SUZ12 - and thereby formation of the PRC2, is positively regulated in growing cells by E2F1, E2F2 and E2F3 (Weinmann et al. 2001, Bracken et al. 2003). H3K27Me3 mark serves as a docking site for the Polycomb repressor complex 1 (PRC1) that contains BMI1 (PCGF4) and is therefore named PRC1.4, leading to the repression of transcription of p16-INK4A and p14-ARF from the CDKN2A locus, where PCR1.4 mediated repression of p14-ARF transcription in humans may be context dependent (Voncken et al. 2005, Dietrich et al. 2007, Agherbi et al. 2009, Gao et al. 2012). MAPKAPK2 and MAPKAPK3, activated downstream of the MAP3K5-p38 MAPK cascade, phosphorylate BMI1 of the PRC1.4 complex, leading to dissociation of PRC1.4 complex from the CDKN2A locus and upregulation of p14-ARF transcription (Voncken et al. 2005). AP-1 transcription factor, formed as a result of MAP3K5-JNK signaling, as well as RAS signaling, binds the promoter of KDM6B (JMJD3) gene and stimulates KDM6B expression. KDM6B is a histone demethylase that removes H3K27Me3 mark i.e. demethylates lysine K28 of HIST1H3A, thereby preventing PRC1.4 binding to the CDKN2A locus and allowing transcription of p16-INK4A (Agger et al. 2009, Barradas et al. 2009, Lin et al. 2012).
p16-INK4A inhibits phosphorylation-mediated inactivation of RB family members by CDK4 and CDK6, leading to cell cycle arrest (Serrano et al. 1993). p14-ARF inhibits MDM2-mediated degradation of TP53 (p53) (Zhang et al. 1998), which also contributes to cell cycle arrest in cells undergoing oxidative stress. In addition, phosphorylation of TP53 by MAPKAPK5 (PRAK) activated downstream of MAP3K5-p38 MAPK signaling, activates TP53 and contributes to cellular senescence (Sun et al. 2007).
Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
The culture medium of senescent cells in enriched in secreted proteins when compared with the culture medium of quiescent i.e. presenescent cells and these secreted proteins constitute the so-called senescence-associated secretory phenotype (SASP), also known as the senescence messaging secretome (SMS). SASP components include inflammatory and immune-modulatory cytokines (e.g. IL6 and IL8), growth factors (e.g. IGFBPs), shed cell surface molecules (e.g. TNF receptors) and survival factors. While the SASP exhibits a wide ranging profile, it is not significantly affected by the type of senescence trigger (oncogenic signalling, oxidative stress or DNA damage) or the cell type (epithelial vs. mesenchymal) (Coppe et al. 2008). However, as both oxidative stress and oncogenic signaling induce DNA damage, the persistent DNA damage may be a deciding SASP initiator (Rodier et al. 2009). SASP components function in an autocrine manner, reinforcing the senescent phenotype (Kuilman et al. 2008, Acosta et al. 2008), and in the paracrine manner, where they may promote epithelial-to-mesenchymal transition (EMT) and malignancy in the nearby premalignant or malignant cells (Coppe et al. 2008). Interleukin-1-alpha (IL1A), a minor SASP component whose transcription is stimulated by the AP-1 (FOS:JUN) complex (Bailly et al. 1996), can cause paracrine senescence through IL1 and inflammasome signaling (Acosta et al. 2013).
Here, transcriptional regulatory processes that mediate the SASP are annotated. DNA damage triggers ATM-mediated activation of TP53, resulting in the increased level of CDKN1A (p21). CDKN1A-mediated inhibition of CDK2 prevents phosphorylation and inactivation of the Cdh1:APC/C complex, allowing it to ubiquitinate and target for degradation EHMT1 and EHMT2 histone methyltransferases. As EHMT1 and EHMT2 methylate and silence the promoters of IL6 and IL8 genes, degradation of these methyltransferases relieves the inhibition of IL6 and IL8 transcription (Takahashi et al. 2012). In addition, oncogenic RAS signaling activates the CEBPB (C/EBP-beta) transcription factor (Nakajima et al. 1993, Lee et al. 2010), which binds promoters of IL6 and IL8 genes and stimulates their transcription (Kuilman et al. 2008, Lee et al. 2010). CEBPB also stimulates the transcription of CDKN2B (p15-INK4B), reinforcing the cell cycle arrest (Kuilman et al. 2008). CEBPB transcription factor has three isoforms, due to three alternative translation start sites. The CEBPB-1 isoform (C/EBP-beta-1) seems to be exclusively involved in growth arrest and senescence, while the CEBPB-2 (C/EBP-beta-2) isoform may promote cellular proliferation (Atwood and Sealy 2010 and 2011). IL6 signaling stimulates the transcription of CEBPB (Niehof et al. 2001), creating a positive feedback loop (Kuilman et al. 2009, Lee et al. 2010). NF-kappa-B transcription factor is also activated in senescence (Chien et al. 2011) through IL1 signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009). NF-kappa-B binds IL6 and IL8 promoters and cooperates with CEBPB transcription factor in the induction of IL6 and IL8 transcription (Matsusaka et al. 1993, Acosta et al. 2008). Besides IL6 and IL8, their receptors are also upregulated in senescence (Kuilman et al. 2008, Acosta et al. 2008) and IL6 and IL8 may be master regulators of the SASP.
IGFBP7 is also an SASP component that is upregulated in response to oncogenic RAS-RAF-MAPK signaling and oxidative stress, as its transcription is directly stimulated by the AP-1 (JUN:FOS) transcription factor. IGFBP7 negatively regulates RAS-RAF (BRAF)-MAPK signaling and is important for the establishment of senescence in melanocytes (Wajapeyee et al. 2008).
Please refer to Young and Narita 2009 for a recent review.
PTK6 (BRK) is an oncogenic non-receptor tyrosine kinase that functions downstream of ERBB2 (HER2) (Xiang et al. 2008, Peng et al. 2015) and other receptor tyrosine kinases, such as EGFR (Kamalati et al. 1996) and MET (Castro and Lange 2010). Since ERBB2 forms heterodimers with EGFR and since MET can heterodimerize with both ERBB2 and EGFR (Tanizaki et al. 2011), it is not clear if MET and EGFR activate PTK6 directly or act through ERBB2. Levels of PTK6 increase under hypoxic conditions (Regan Anderson et al. 2013, Pires et al. 2014). The kinase activity of PTK6 is negatively regulated by PTPN1 phosphatase (Fan et al. 2013) and SRMS kinase (Fan et al. 2015), as well as the STAT3 target SOCS3 (Gao et al. 2012).
PTK6 activates STAT3-mediated transcription (Ikeda et al. 2009, Ikeda et al. 2010) and may also activate STAT5-mediated transcription (Ikeda et al. 2011). PTK6 promotes cell motility and migration by regulating the activity of RHO GTPases RAC1 (Chen et al. 2004) and RHOA (Shen et al. 2008), and possibly by affecting motility-related kinesins (Lukong and Richard 2008). PTK6 crosstalks with AKT1 (Zhang et al. 2005, Zheng et al. 2010) and RAS signaling cascades (Shen et al. 2008, Ono et al. 2014) and may be involved in MAPK7 (ERK5) activation (Ostrander et al. 2007, Zheng et al. 2012). PTK6 enhances EGFR signaling by inhibiting EGFR down-regulation (Kang et al. 2010, Li et al. 2012, Kang and Lee 2013). PTK6 may also enhance signaling by IGF1R (Fan et al. 2013) and ERBB3 (Kamalati et al. 2000).
PTK6 promotes cell cycle progression by phosphorylating and inactivating CDK inhibitor CDKN1B (p27) (Patel et al. 2015).
PTK6 activity is upregulated in osteopontin (OPN or SPP1)-mediated signaling, leading to increased VEGF expression via PTK6/NF-kappaB/ATF4 signaling path. PTK6 may therefore play a role in VEGF-dependent tumor angiogenesis (Chakraborty et al. 2008).
PTK6 binds and phosphorylates several nuclear RNA-binding proteins, including SAM68 family members (KHDRSB1, KHDRSB2 and KHDRSB3) (Derry et al. 2000, Haegebarth et al. 2004, Lukong et al. 2005) and SFPQ (PSF) (Lukong et al. 2009). The biological role of PTK6 in RNA processing is not known.
For a review of PTK6 function, please refer to Goel and Lukong 2015.
In the nucleus, SMAD2/3:SMAD4 heterotrimer complex acts as a transcriptional regulator. The activity of SMAD2/3 complex is regulated both positively and negatively by association with other transcription factors (Chen et al. 2002, Varelas et al. 2008, Stroschein et al. 1999, Wotton et al. 1999). In addition, the activity of SMAD2/3:SMAD4 complex can be inhibited by nuclear protein phosphatases and ubiquitin ligases (Lin et al. 2006, Dupont et al. 2009).
The pRB C-terminus contains a cluster of seven candidate in vivo cdk phosphorylation sites (residues 795, 807, 811, 821, and 826) and is phosphorylated in vitro by cyclin A, cyclin E, and cyclin D-associated kinases.
Dephoshorylation of RB1 by the PP2A complex containing the regulatory subunit PPP2R3B (PR70) (Magenta et al. 2008) is needed for loading of RB1 to the DNA damage sites during S phase of the cell cycle. RB1 suppresses replication of damaged DNA during S phase (Knudsen et al. 2000, Avni et al. 2003).
At the beginning of this reaction, 1 molecule of 'RNA primer-DNA primer:origin duplex' is present. At the end of this reaction, 1 molecule of 'DNA polymerase alpha:primase', and 1 molecule of 'RNA primer-DNA primer:origin duplex with DNA damage' are present. This reaction takes place in the 'nucleus' (Gambus et al. 2009, Remus et al. 2009, Chattopadhyay et al.2007, Fien et al. 2004).
This event is inferred from the fission yeast. Cyclin B activity is thought to inhibit pre-RC formation by first associating with ORC during DNA replication.
This set of events is inferred from annotated events in Drosophila.
Rb1 is normally hyperphosphorylated by CycD/CDK4/CDK6 and Cyclin E/CDK2 for transition into S-phase. PP2A can then reverse this reaction, in this case, in response to DNA damage induced checkpoint.
At G1 entry from G0, p130 (RBL2) is phosphorylated on three threonine and serine residues by cyclin D1 dependent kinases CDK4 and/or CDK6, leading to dissociation of p130 (RBL2) from complexes it formed with E2F4 or E2F5 and DP1 or DP2. This is thought to promote translocation of E2F4 and E2F5, which lack nuclear localization signals, to the cytosol, allowing activating E2Fs (E2F1, E2F2 and E2F3) to bind E2F promoters and activate transcription of genes needed for G1 progression.
In late G1, cyclin D dependent kinases CDK4 and CDK6 phosphorylate RBL1 (p107) on four serine and threonine residues (S964, S975, T369 and S640), leading to dissociation of phosphorylated RBL1 (p107) from E2F4 in complex with either DP-1 or DP-2. E2F4, which lacks nuclear localization signal, is then thought to translocate to the cytosol, allowing E2F promoter sites to become occupied by activating E2Fs (E2F1, E2F2, and E2F3), resulting in transcription of E2F targets needed for cell cycle progression.
p130 (RBL2) in complex with E2F4 or E2F5 and DP1 or DP2 recruits histone deacetylase HDAC1, probably in complex with other chromatin modification factors, and represses transcription of E2F target promoters during G0 in quiescent cells.
p107 (RBL1) in complex with E2F4 and DP1 or DP2 recruits histone deacetylase HDAC1 (possibly in complex with other chromatin modification proteins) through LXCXE-like motif, shared by pocket proteins, to repress transcription of E2F target genes in early G1.
In G0 and early G1, p130 (RBL2) bound to E2F4 or E2F5 and DP1 or DP2 associates with the MuvB complex, consisting of LIN9, LIN37, LIN52, LIN54 and RBBP4 to form evolutionarily conserved DREAM complex. Phosphorylation of LIN52 on serine residue S28 is critical for association of MuvB complex with p130 (RBL2).
LIN52 subunit of MuvB complex is phosphorylated by the protein kinase DYRK1A on the serine residue S28, promoting association of MuvB with p130 (RBL2). From model organism studies, DYRK proteins are known to function in cell cycle regulation, differentiation and stress response.
Dephosphorylation of p107 (RBL1) by PP2A complex containing either PPP2R3B (B" beta) or PPP2R2A (B alpha) regulatory subunit plays a role in maintaining the equilibrium of hyperphosphorylated and hypophosphorylated p107 (RBL1), through counteracting action of cyclin dependent kinases (CDKs) throughout the cell cycle. It is assumed that PP2A dephosphorylates p107 (RBL1) on all four phosphorylation sites, but further experiments are needed to confirm this.
Dephosphorylation of p130 (RBL2) by PP2A complex containing either PPP2R3B (B" beta) or PPP2R2A (B alpha) regulatory subunit plays a role in maintaining the equilibrium of hyperphosphorylated and hypophosphorylated p130 (RBL2), through counteracting action of cyclin dependent kinases (CDKs). It is assumed that PP2A dephosphorylates p130 (RBL2) on all three phosphorylation sites, but further experiments are needed to confirm this.
p130 (RBL2) in complex with E2F4/5 and DP1/2 binds to cyclin A or cyclin E in complex with CDK2 through its conserved LFG pocket domain motif and amino terminus, leading to inhibition of CDK2 kinase activity and suppression of cellular growth.
p130 (RBL2) is able to bind complexes of CDK2 with either cyclin A or cyclin E through the cyclin-binding LFG motif within the pocket domain, which is conserved in p107 (RBL1) and p21/WAF1/Cip1 family of cyclin-dependent kinases. In addition to LFG motif, amino terminal region of p130 (RBL2), conserved in p107 (RBL1), is necessary for inhibition of CDK2 kinase activity. Presence of E2F is not required for this interaction.
p107 (RBL1) in complex with E2F4 and DP1/2 binds to cyclin A or cyclin E in complex with CDK2 through its conserved LFG pocket domain motif and amino terminus, leading to inhibition of CDK2 kinase activity and suppression of cellular growth.
p107 (RBL1) is able to bind complexes of CDK2 with either cyclin A or cyclin E, through cyclin-binding LFG motif in the pocket domain, which is conserved in p130 (RBL2) and p21/WAF1/Cip1 family of cyclin-dependent kinase inhibitors. In addition to the LFG motif, the amino terminal sequence conserved in the p107 (RBL1) and p130 (RBL2) is needed for inhibition of CDK2 kinase activity. Presence of E2F is not required for this interaction.
Phosphorylated p130 (RBL2) binds SCF (Skp2) ubiquitin ligase in complex with Cks1. Phosphorylation of p130 (RBL2) serine residue S672 by CDK4/6 is critical for this interaction.
As quiescent G0 cells reenter the cell cycle, p130 (RBL2) is phosphorylated by CDK4/6. This phosphorylated p130 (RBL2) binds ubiquitin ligase SCF (Skp2) in complex with Cks1, and is subsequently ubiquitinated and degraded similarly to p27, which is another target of SCF (Skp2).
Prior to mitogen activation, the inhibitory proteins of the INK4 family (p15, p16, p18, and p19) associate with the catalytic domains of free CDK4 and CDK6, preventing their association with D type cyclins (CCND1, CCND2 and CCND3), and thus their activation (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995). Inactivation and defects of RB1 strongly upregulate p16-INK4A (Parry et al. 1995).
p27 translocates to the nucleoplasm where it associates with CyclinE:Cdk2 complexes. Localization of p27 to the nucleus is necessary to inhibit Cdk activation by Cdk-activating kinase.
The interaction between the Skp2 subunit of the SCF(Skp2) complex and p27 is dependent upon Cdk2:Cyclin A/E mediated phosphorylation of p27 at Thr 187 (Carrano et al, 1999; Tsvetkov et al, 1999). There is evidence that Cyclin A/B:Cdk1 can also bind and phosphorylate p27 on Thr 187 (Nakayama et al., 2004). This phosphorylation is also essential for the subsequent ubiquitination of p27.
The accessory protein, Cks1 promotes efficient interaction between phosphorylated p27 and the SCF (Skp2) complex (Ganoth et al., 2001; Spruck et al., 2001). Cks1 binds to Skp2 in the leucine-rich repeat (LRR) domain and C-terminal tail (Hao et al., 2005). The phosphorylated Thr187 side chain of p27 associates with a phosphate binding site on Cks1, and the side chain containing Glu185 is positioned in the interface between Skp2 and Cks1 where it interacts with both (Hao et al., 2005).
Binding of the MYC:MAX heterodimer to MYC response elements in the first and second intron of the CDC25A gene activates CDC25A transcription in mid to late G1 (Galaktionov et al. 1996). Transcription of the CDC25A gene can be directly activated by E2F1 (DeGregori et al. 1995, Vigo et al. 1999). Transcription of the CDC25A gene is directly inhibited by the DREAM complex (Litovchick et al. 2007).
Phosphorylation of cyclin-dependent kinases (CDKs) by the CDK-activating kinase (CAK) is required for the activation of the CDK kinase activity. The association of p21/p27 with the Cyclin A/E:Cdk2 complex prevents CAK mediated phosphorylation of Cdk2 (Aprelikova et al., 1995).
pRB contains, in its C terminus, a cyclin-cdk interaction motif like that found in E2F1 and p21 that enables it to be recognized and phosphorylated by cyclin-cdk complexes.
Phosphorylation of p27Kip1 at T157 and of p21Cip1 at T145 by AKT leads to their retention in the cytoplasm, segregating these cyclin-dependent kinase (CDK) inhibitors from cyclin-CDK complexes.
DNA polymerase alpha:primase is comprised of four subunits, p180, p70, p58, and p49. The two primase subunits, p58 and p49, form a tight complex. The p49 subunit contains the DNA primase activity and one role of p58 appears to be tethering p49 to p180, the DNA polymerase catalytic subunit. The fourth subunit, p70, binds p180 and may tether the DNA polymerase alpha:primase complex to Cdc45.
After pre-RC assembly and Cdc45 association with the origin of replication, Replication Protein A (RPA) also associates with chromatin. RPA is a heterotrimeric complex containing p70, p34, and p11 subunits, and also is required for DNA recombination and DNA repair. The p70 subunit of RPA binds to the primase subunits of Pol alpha:primase. The p70 and p34 subunits of RPA are phosphorylated in a cell cycle-dependent manner. RPA is a single-strand DNA (ssDNA) binding protein and its association with chromatin at this stage suggests that DNA is partially unwound. This suggestion has been confirmed by detection of ssDNA in budding yeast origins of replication using chemical methods.
Once the Mcm2-7 complex has been assembled onto the origin of replication, the next step is the assembly of Cdc45, an essential replication protein, in late G1. The assembly of Cdc45 onto origins of replication forms a complex distinct from the pre-replicative complex, sometimes called the pre-initiation complex. The assembly of Cdc45 onto origins correlates with the time of initiation. Like the Mcm2-7 proteins, Cdc45 binds specifically to origins in the G1 phase of the cell cycle and then to non-origin DNA during S phase and is therefore thought to travel with the replication fork. Indeed, S. cerevisiae Cdc45 is required for DNA replication elongation as well as replication initiation. Cdc45 is required for the association of alpha DNA polymerase:primase with chromatin. Based on this observation and the observation that in S. cerevisiae, cCdc45 has been found in large complexes with some components of Mcm2-7 complex, it has been suggested that Cdc45 plays a scaffolding role at the replication fork, coupling Pol-alpha:primase to the replication fork through the helicase. Association of Cdc45 with origin DNA is regulated in the cell cycle and its association is dependent on the activity of cyclin-dependent kinases but not the Cdc7/Dbf4 kinase. In Xenopus egg extracts, association of Cdc45 with chromatin is dependent on Xmus101. TopBP1, the human homolog of Xmus1, is essential for DNA replication and interacts with DNA polymerase epsilon, one of the polymerases involved in replicating the genome. TopBP1 homologs have been found in S. cerevisiae and S. pombe. Sld3, an additional protein required for Cdc45 association with chromatin in S. cerevisiae and S. pombe, has no known human homolog.
At the beginning of this reaction, 1 molecule of 'Mcm10:active pre-replicative complex', 1 molecule of 'DDK', and 1 molecule of 'CDK' are present. At the end of this reaction, 1 molecule of 'CDK:DDK:Mcm10:pre-replicative complex' is present.
MCM10 is required for human DNA replication. In S. cerevisiae, Mcm10, like Mcm2-7, is required for minichromosome maintenance, but Mcm10 has no sequence homology with these other proteins (Merchant et al., 1997). Genetic studies have demonstrated that Mcm10 is required for DNA replication in S. pombe (Aves et al., 1998) and S. cerevisiae cells (Homesley et al., 2000) and immunodepletion of XlMcm10 interferes with DNA replication in Xenopus egg extracts (Wohlschlegel et al., 2002). Human Mcm10 interacts with chromatin in G1 phase and then dissociates during G2 phase. In S. cerevisiae, Mcm10 has been shown to localize to origins during G1 (Ricke and Bielinsky, 2004), and it may stabilize the association of Mcm2-7 with the pre-replicative complex (Sawyer et al., 2004). This timing of association is consistent with studies that demonstrate that, in Xenopus egg extracts, Mcm10 is required for association of Cdc45, but not Mcm2-7 with chromatin. Biochemical evidence that Mcm10 plays a direct role in the activation of the pre-replicative complex includes the requirement for SpMcm10 in the phosphorylation of the Mcm2-7 complex by DDK (Lee et al., 2004) and the fact that SpMcm10 binds and stimulates DNA polymerase alpha activity (Fien et al., 2004).
At the beginning of this reaction, 1 molecule of 'Mcm10:pre-replicative complex' is present. At the end of this reaction, 1 molecule of 'Mcm10:active pre-replicative complex', and 1 molecule of 'CDT1' are present.
At the beginning of this reaction, 1 molecule of 'Mcm2-7 complex', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'phosphorylated Mcm2-7 complex', and 1 molecule of 'ADP' are present.
This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'DDK'.
At the beginning of this reaction, 1 molecule of 'origin of replication', and 1 molecule of 'DNA polymerase epsilon' are present. At the end of this reaction, 1 molecule of 'DNA polymerase epsilon:origin complex' is present.
The E-type cyclins and Cyclin Dependent Kinase 2 control the transition from G1 to S phase. Cdk2 is competent to carry out the necessary reactions only when complexed with Cyclin E.
WEE1 phosphorylates CDK2, inhibiting entry into S-phase (Watanabe et al., 1995; Wu et al., 2001). WEE1-mediated phosphorylation of CDK2 is enhanced in the presence of CABLES1, which can form a complex with CDK2 bound to cyclin E (CCNE) or cyclin A (CCNA) (Wu et al. 2001).
At the beginning of this reaction, 1 molecule of 'geminin', and 1 molecule of 'CDT1' are present. At the end of this reaction, 1 molecule of 'Cdt1:geminin' is present.
During G1, the activity of cyclin-dependent kinases (CDKs) is controlled by the CDK inhibitors (CKIs) CDKN1A (p21) and CDKN1B (p27), thereby preventing premature entry into S phase (see Guardavaccaro and Pagano, 2006). The efficient recognition and ubiquitination of p27 by the SCF (Skp2) complex requires the formation of a trimeric complex containing p27 and cyclin E/A:Cdk2.
Activated PTK6 (BRK) binds to CDKN1B (p27KIP1) that is in a complex with CDK4 and cyclin D1 (CCND1). Since PTK6 increases cyclin E1 (CCNE1) levels downstream of ERBB2 while decreasing CDKN1B levels, PTK6 probably also associates with CDKN1B bound to the complex of CCNE1 and CDK2 (Xiang et al. 2008).
PTK6 (BRK) phosphorylates CDKN1B (p27KIP1) bound to the complex of CDK4 and CCND1 (cyclin D1) on tyrosine residue Y88 and possibly other tyrosines (e.g. Y89) (Patel et al. 2015). Based on the finding that PTK6 promotes ERBB2-induced increase in cyclin E1 (CCNE1) levels and decrease in CDKN1B levels (Xiang et al. 2008), and supported by the analogy with other SRC family kinases that phosphorylate CDKN1B (Grimmler et al. 2007), PTK6 is likely to also phosphorylate CDKN1B bound to the complex of CCNE1 and CDK2. Phosphorylation of CDKN1B (p27KIP1) on tyrosine residue Y88 by SRC family kinases dislodges the 3-10 helix of CDKN1B from the active site of CDK2 or CDK4, thus converting CDKN1B from a bound inhibitor to a bound non-inhibitor (Grimmler et al. 2007, Ray et al. 2009).
The cyclin dependent kinase CDK4 or CDK6 forms a complex with one of the cyclin D family (CCND) members: cyclin D1 (CCND1), cyclin D2 (CCND2) or cyclin D3 (CCND3) (Matsushime et al. 1992, Meyerson and Harlow 1994, La Baer et al. 1997, Bagui et al. 2003, Cerqueira et al. 2014). This association is regulated by mitogenic pathways (Cheng et al. 1998, Depoortere et al. 1998). While the binding of Cip/Kip CDK-inhibitors (CDKIs) (CDKNA1 - p21Cip, CDKN1B - p27Kip or CDKN1C - p57Kip2) stabilizes CDK4/6:CCND complexes by decreasing their dissociation rate (La Baer et al. 1997; reviewed by Sherr and Roberts 1999), CIP/KIP CDKIs are not needed for binding of CDK4 or CDK6 to CCNDs and activity of CDK4/6:CCND complexes (Bagui et al. 2000, Sugimoto et al. 2002, Bagui et al. 2003, Cerqueira et al. 2014; reviewed by Bockstaele et al 2006).
Binding of CDK inhibitors of the Cip/Kip family, CDKNA1 (p21Cip), CDKN1B (p27Kip) or CDKN1C (p57Kip2) to the complex of CDK4 or CDK6 and cyclin D family members (CCND1, CCND2 or CCND3), inhibits kinase activity of the CDK4/6:CCND complexes but at the same time increases their stability and, hence, their abundance (La Baer et al. 1997, Bagui et al. 2003, Cerqueira et al. 2014; reviewed by Bockstaele et al. 2006). Based on structural studies of CDKN1B, Cip/Kip inhibitors simultaneously interact with CDK4/6 and CCNDs (Liu et al. 2010). Phosphorylation of CDKN1B on threonine residues T157 and T198 by activated AKT in early G1 may precede binding of CDKN1B to CDK4/6:CCND complexes (Larrea et al. 2008).
Phosphorylation of Cip/Kip cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip), CDKN1B (p27Kip1) and CDKN1C (p57Kip2) on conserved tyrosine residues Y77, Y88 and Y91, respectively, can convert them from bound inhbitors to bound non-inhibitors of CDK4 or CDK6 complexes with D cyclins by dislodging them from the active site of CDK4 or CDK6. This mechanism was studied in most detail on the example of CDKN1B associated with the CDK2:CCNA complex (Grimmler et al. 2007) and the CDK4:CCND1 complex (James et al. 2008, Patel et al. 2015). For a review of this topic, please refer to Blain 2008. CDKN1A can be phosphorylated at tyrosine residue Y77 by protein tyrosine kinase ABL1 (Hukkelhoven et al. 2012). CDKN1B can be phosphorylated at tyrosine residue Y88, and probably also at the adjacent Y89, by protein tyrosine kinases ABL1 (Grimmler et al. 2007, James et al. 2008, Ray et al. 2009, Ou et al. 2011), LYN (Grimmler et al. 2007), SRC (Larrea et al. 2008), JAK2 (Jakel et al. 2011) and PTK6 (Patel et al. 2015). CDKN1C can be phosphorylated at tyrosine residue Y91 by protein tyrosine kinase ABL1 (Borriello et al. 2011). Dislodgment of the tyrosine phosphorylated 3-10 helix of Cip/Kip CDK inhibitors from the active site of cyclin D-bound CDK4 or CDK6 results in increased catalytic activity of CDK4 or CDK6 by allowing ATP binding to the active site, but also by enabling activating phosphorylation of the T-loop of CDK4 or CDK6 phosphorylation by CDK7 in complex with cyclin H (Ray et al. 2009). SRC-mediated phosphorylation of CDKN1B on tyrosine residue Y88 was shown to reduce protein stability of CDKN1B (Chu et al. 2007). Without overexpression of BCR-ABL or SRC-family tyrosine kinases in several cell systems, tyrosine phosphorylated p27 is either undetectable or a very low abundance species (Ishida et al. 2000, Jaimes et al. 2008, Grimmler et al. 2007) that does not bind preferentially to CDK4 (Jaimes et al. 2008). Therefore, tyrosine phosphorylation of p27 is unlikely to be the sole explanation of the full activity of p27-bound CDK4:CCND complexes reported in previous studies (Blain et al. 1997, Coulonval et al. 2003, Bockstaele et al. 2006). It has been proposed that stoichiometry of the Cip/Kip complex with CDK4 or CDK6 and cyclin D, in addition to or alternative to tyrosine phosphorylation of Cip/Kip CDK inhibitors, determines their inhibitory role where binding of more than one molecule of CDKN1A, CDKN1B or CDKN1C would be needed to achieve inhibition of the CDK4/6:CCND complex (reviewed by Paternot et al. 2010).
T-loop phosphorylation of CDK4 and CDK6 on threonine residues T172 and T177, respectively, is necessary for catalytic activity of complexes of CDK4 and CDK6 with D-type cyclins (CCND1, CCND2 and CCND3) (Kato, Matsuoka, Strom and Sherr 1994, Merzel-Schachter et al. 2013, Bisteau et al. 2013). These phosphorylations depend on prior D type cyclin binding (Kato, Matsuoka, Polyak et al. 1994, Bockstaele et al. 2006). The T-loop phosphorylation is not precluded by the association of CDK4/6:CCND complexes to Cip/Kip cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip) and CDKN1B (p27Kip1), however high expression levels of CDKN1B reduce the T172 phosphorylation of CDK4 (Kato, Matsuoka, Polyak et al. 1994, Bockstaele et al. 2006, Ray et al. 2009). Phosphorylation at tyrosine residue Y89 of CDKN1B (p27Kip1) bound to CDK4:CCND complexes was found to be necessary for phosphorylation of CDK4 by the CAK complex (composed of CDK7, CCNH and MAT1) in vitro, but not for the phosphorylation by CSK1 of S. pombe (Ray et al. 2009). T-loop phosphorylations of CDK4 and CDK6 are differentially regulated (Bockstaele et al. 2009). Especially, the T172 phosphorylation of CDK4 is strictly controlled by mitogenic and antimitogenic pathways (Paternot and Roger 2009), and it can be differentially regulated in cyclin D1:CDK4 and cyclin D3:CDK4 complexes (reviewed by Paternot et al. 2010). The T-loop T172 phosphorylation motif of CDK4 differs from the other cell cycle CDKs, including CDK6, by the presence of an adjacent proline residue (P173) that is evolutionarily conserved. This proline residue is required for T172 phosphorylation of CDK4 in vivo, but not for its in vitro phosphorylation by CAK. This indicates that CDK4 might be activated by other proline-directed kinases in vivo (Bockstaele et al. 2009). Nevertheless, in HCT116 colon carcinoma cell line, the activity of CDK7 is required for the T172 phosphorylation of CDK4 and the activity of CDK4/6:CCND complexes (Merzel Schachter et al. 2013, Bisteau et al. 2013). T170 phosphorylation of CDK7 facilitates the activity of CAK on CDK4 (Merzel Schachter et al. 2013). However, CDK7 inhibition in HCT116 cells does not preclude the T172 phosphorylation of CDK4:CCND complexes that are not associated with CDKN1A (Bisteau et al. 2013). Phosphorylation of CDKN1A at serine residue S130 by CDK4/6 and CDK2 has been implicated as a pre-requisite for CAK-mediated phosphorylation of CDKN1A-bound CDK4 (Bisteau et al. 2013). Other kinases involved in phosphorylation of CDK4 at T172 remain to be defined (Bockstaele et al. 2009, Bisteau et al. 2013, reviewed by Paternot et al. 2010).
E2F1 directly stimulates transcription of the CDC6 gene (Yan et al., 1998; Ohtani et al., 1998). CDC6 is required to recruit the MCM2-7 replication helicases. Transcription of the CDC6 gene is directly repressed by the DREAM complex (Litovchick et al. 2007).
E2F1 binds to E2F binding sites in the promoter of the CDC6 gene (Yan et al., 1998; Ohtani et al., 1998). CDC6 is required to recruit the MCM2-7 replication helicases.
E2F1 binds to E2F binding sites in the promoter of the POLA1 gene, stimulating POLA1 transcription. POLA1 encodes the catalytic subunit p180 of the DNA polymerase alpha (DeGregori et al. 1995, Giangrande et al. 2004). Activation of POLA1 by E2F1 has also been demonstrated in Drosophila (Ohtani and Nevins 1994).
E2F1 binds to E2F binding sites in the promoter of the POLA1 gene, encoding the DNA polymerase alpha catalytic subunit p180 (DeGregori et al. 1995, Giangrande et al. 2004).
E2F1 binds to E2F binding sites in the promoter of the PCNA gene, encoding the proliferating cell nuclear antigen, a component of the DNA polymerase complex involved in eukaryotic DNA replication (DeGregori et al. 1995, Li et al. 2003).
E2F1 directly stimulates transcription of the PCNA gene, which encodes the proliferating cell nuclear antigen, a component of the DNA polymerase complex involved in eukaryotic DNA replication (DeGregori et al. 1995, Li et al. 2003). The PCNA gene transcription is directly repressed by the DREAM complex (Litovchick et al. 2007).
E2F1 binds to E2F binding sites in the promoter of the ORC1 gene (Ohtani et al. 1996, Ohtani et al. 1998). It has been observed in Drosophila that E2F1 regulated expression of Orc1 stimulates ORC1-6 complex formation and binding to the origin of replication (Asano and Wharton, 1999).
E2F1 directly stimulates transcription of the ORC1 gene (Ohtani et al. 1996, Ohtani et al. 1998). E2F1 regulated expression of Orc1 stimulates ORC1-6 complex formation and binding to the origin of replication in Drosophila (Asano and Wharton, 1999).
E2F1 directly stimulates transcription of the CCNE1 gene, encoding cyclin E1 (DeGregori et al. 1995, Ohtani et al. 1995).Cyclin E proteins play an important role in the transition from G1 to S-phase by associating with CDK2.
E2F1 binds to E2F binding sites in the promoter of the DHFR gene, encoding dihydrofolate reductase. DHFR is involved in folate metabolism and synthesis of DNA bases (DeGregori et al. 1995, Wells et al. 1997, Darbinian et al. 1999).
E2F1 directly stimulates transcription of the DHFR gene, encoding dihydrofolate reductase. DHFR is involved in folate metabolism and synthesis of DNA bases (DeGregori et al. 1995, Wells et al. 1997, Darbinian et al. 1999).
E2F1 directly stimulates transcription of the CDC45 gene (Arata et al. 2000), encoding Cell division control protein 45 homolog, which is required for initiation of DNA replication.
E2F1 binds to E2F binding sites in the promoter of the CDK1 gene, encoding cyclin-dependent kinase 1 (Cdc2) (Furukawa et al. 1994, DeGregori et al. 1995, Zhu et al. 2004).
E2F1 directly stimulates transcription of the CDK1 gene, encoding cyclin-dependent kinase 1 (Cdc2) (Furukawa et al. 1994, DeGregori et al. 1995, Zhu et al. 2004). Transcription of the CDK1 gene is directly inhibited by complexes of HDAC1 and RBL1 (p107) or RBL2 (p130) in G1 and G0, respectively (Rayman et al. 2002).
E2F1 binds to E2F binding sites in the promoter of the RRM2 gene, encoding Ribonucleoside-diphosphate reductase subunit M2 (DeGregori et al. 1995, Giangrande et al. 2004).
E2F1 directly stimulates transcription of the RRM2 gene, encoding Ribonucleoside-diphosphate reductase subunit M2 (DeGregori et al. 1995, Giangrande et al. 2004). Binding of E2F6 to the RRM2 gene promoter inhibits RRM2 transcription (Bertoli et al. 2013).
E2F1 binds to E2F binding sites in the promoter of the TK1 gene, encoding thymidine kinase (Dou et al. 1994, DeGregori et al. 1995, Giangrande et al. 2004).
Expression of the TYMS gene, encoding thymidylate synthase, is positively regulated by E2F1, but direct regulation has not been demonstrated (DeGregori et al. 1995).
Transcription of the E2F1 gene is directly inhibited by the DREAM complex (Litovchick et al. 2007). E2F1 transcription is also directly inhibited by the complex of HDAC1 and RBL1 (p107) or RBL2 (p130) (Rayman et al. 2002).
In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the E2F1 gene (Rayman et al. 2002).
In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the MYBL2 gene (Rayman et al. 2002).
In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the CDK1 gene (Rayman et al. 2002).
In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the CCNA2 gene (Rayman et al. 2002).
In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 bind the promoter of the CCNA2 gene (Rayman et al. 2002).
In G0 and early G1, complexes containing p130 (RBL2) and p107 (RBL1), respectively, and histone deacetylase HDAC1 directly inhibit transcription from the MYBL2 gene (Rayman et al. 2002).
RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, binds to E2F transcription factors E2F1, E2F2 and E2F3, presumably heterodimerized with TFDP1 or TFDP2. The interaction involves the pocket domain of RB1. RB1 binding inhibits transcriptional activity of E2F1/2/3:TFDP1/2 complexes, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1/2/3:TFDP1/2 complexes. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1/2/3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997).
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pre-replicative
complex:CDC45:RPA1-4pre-replicative
complex:CDC45pre-replicative
complexB:CDK1:ORC:origin
of replicationalpha:primase:DNA polymerase alpha:origin
complexepsilon:origin
complexpre-replicative
complexOncogenic signals trigger transcription of CDKN2A locus tumor suppressor genes: p16-INK4A and p14-ARF. p16-INK4A and p14-ARF share exons 2 and 3, but are expressed from different promoters and use different reading frames (Quelle et al. 1995). Therefore, while their mRNAs are homologous and are both translationally inhibited by miR-24 microRNA (Lal et al. 2008, To et al. 2012), they share no similarity at the amino acid sequence level and perform distinct functions in the cell. p16-INK4A acts as the inhibitor of cyclin-dependent kinases CDK4 and CDK6 which phosphorylate and inhibit RB1 protein thereby promoting G1 to S transition and cell cycle progression (Serrano et al. 1993). Increased p16-INK4A level leads to hypophosphorylation of RB1, allowing RB1 to inhibit transcription of E2F1, E2F2 and E2F3-target genes that are needed for cell cycle progression, which results in cell cycle arrest in G1 phase. p14-ARF binds and destabilizes MDM2 ubiquitin ligase (Zhang et al. 1998), responsible for ubiquitination and degradation of TP53 (p53) tumor suppressor protein (Wu et al. 1993, Fuchs et al. 1998, Fang et al. 2000). Therefore, increased p14-ARF level leads to increased level of TP53 and increased expression of TP53 target genes, such as p21, which triggers p53-mediated cell cycle arrest and, depending on other factors, may also lead to p53-mediated apoptosis. CDKN2B locus, which encodes an inhibitor of CDK4 and CDK6, p15-INK4B, is located in the vicinity of CDKN2A locus, at the chromosome band 9p21. p15-INK4B, together with p16-INK4A, contributes to senescence of human T-lymphocytes (Erickson et al. 1998) and mouse fibroblasts (Malumbres et al. 2000). SMAD3, activated by TGF-beta-1 signaling, controls senescence in the mouse multistage carcinogenesis model through regulation of MYC and p15-INK4B gene expression (Vijayachandra et al. 2003). TGF-beta-induced p15-INK4B expression is also important for the senescence of hepatocellular carcinoma cell lines (Senturk et al. 2010).
MAP kinases MAPK1 (ERK2) and MAPK3 (ERK1), which are activated by RAS signaling, phosphorylate ETS1 and ETS2 transcription factors in the nucleus (Yang et al. 1996, Seidel et al. 2002, Foulds et al. 2004, Nelson et al. 2010). Phosphorylated ETS1 and ETS2 are able to bind RAS response elements (RREs) in the CDKN2A locus and stimulate p16-INK4A transcription (Ohtani et al. 2004). At the same time, activated ERKs (MAPK1 i.e. ERK2 and MAPK3 i.e. ERK1) phosphorylate ERF, the repressor of ETS2 transcription, which leads to translocation of ERF to the cytosol and increased transcription of ETS2 (Sgouras et al. 1995, Le Gallic et al. 2004). ETS2 can be sequestered and inhibited by binding to ID1, resulting in inhibition of p16-INK4A transcription (Ohtani et al. 2004).
Transcription of p14-ARF is stimulated by binding of E2F transcription factors (E2F1, E2F2 or E2F3) in complex with SP1 to p14-ARF promoter (Parisi et al. 2002).
Oncogenic RAS signaling affects mitochondrial metabolism through an unknown mechanism, leading to increased generation of reactive oxygen species (ROS), which triggers oxidative stress induced senescence pathway. In addition, increased rate of cell division that is one of the consequences of oncogenic signaling, leads to telomere shortening which acts as another senescence trigger.
MAP3K5 phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997, Takekawa et al. 2005), which act as p38 MAPK kinases, as well as MAP2K4 (SEK1) (Ichijo et al. 1997, Matsuura et al. 2002), which, together with MAP2K7 (MKK7), acts as a JNK kinase.
MKK3 and MKK6 phosphorylate and activate p38 MAPK alpha (MAPK14) and beta (MAPK11) (Raingeaud et al. 1996), enabling p38 MAPKs to phosphorylate and activate MAPKAPK2 (MK2) and MAPKAPK3 (MK3) (Ben-Levy et al. 1995, Clifton et al. 1996, McLaughlin et al. 1996, Sithanandam et al. 1996, Meng et al. 2002, Lukas et al. 2004, White et al. 2007), as well as MAPKAPK5 (PRAK) (New et al. 1998 and 2003, Sun et al. 2007).
Phosphorylation of JNKs (MAPK8, MAPK9 and MAPK10) by MAP3K5-activated MAP2K4 (Deacon and Blank 1997, Fleming et al. 2000) allows JNKs to migrate to the nucleus (Mizukami et al. 1997) where they phosphorylate JUN. Phosphorylated JUN binds FOS phosphorylated by ERK1 or ERK2, downstream of activated RAS (Okazaki and Sagata 1995, Murphy et al. 2002), forming the activated protein 1 (AP-1) complex (FOS:JUN heterodimer) (Glover and Harrison 1995, Ainbinder et al. 1997).
Activation of p38 MAPKs and JNKs downstream of MAP3K5 (ASK1) ultimately converges on transcriptional regulation of CDKN2A locus. In dividing cells, nucleosomes bound to the CDKN2A locus are trimethylated on lysine residue 28 of histone H3 (HIST1H3A) by the Polycomb repressor complex 2 (PRC2), creating the H3K27Me3 (Me3K-28-HIST1H3A) mark (Bracken et al. 2007, Kotake et al. 2007). The expression of Polycomb constituents of PRC2 (Kuzmichev et al. 2002) - EZH2, EED and SUZ12 - and thereby formation of the PRC2, is positively regulated in growing cells by E2F1, E2F2 and E2F3 (Weinmann et al. 2001, Bracken et al. 2003). H3K27Me3 mark serves as a docking site for the Polycomb repressor complex 1 (PRC1) that contains BMI1 (PCGF4) and is therefore named PRC1.4, leading to the repression of transcription of p16-INK4A and p14-ARF from the CDKN2A locus, where PCR1.4 mediated repression of p14-ARF transcription in humans may be context dependent (Voncken et al. 2005, Dietrich et al. 2007, Agherbi et al. 2009, Gao et al. 2012). MAPKAPK2 and MAPKAPK3, activated downstream of the MAP3K5-p38 MAPK cascade, phosphorylate BMI1 of the PRC1.4 complex, leading to dissociation of PRC1.4 complex from the CDKN2A locus and upregulation of p14-ARF transcription (Voncken et al. 2005). AP-1 transcription factor, formed as a result of MAP3K5-JNK signaling, as well as RAS signaling, binds the promoter of KDM6B (JMJD3) gene and stimulates KDM6B expression. KDM6B is a histone demethylase that removes H3K27Me3 mark i.e. demethylates lysine K28 of HIST1H3A, thereby preventing PRC1.4 binding to the CDKN2A locus and allowing transcription of p16-INK4A (Agger et al. 2009, Barradas et al. 2009, Lin et al. 2012).
p16-INK4A inhibits phosphorylation-mediated inactivation of RB family members by CDK4 and CDK6, leading to cell cycle arrest (Serrano et al. 1993). p14-ARF inhibits MDM2-mediated degradation of TP53 (p53) (Zhang et al. 1998), which also contributes to cell cycle arrest in cells undergoing oxidative stress. In addition, phosphorylation of TP53 by MAPKAPK5 (PRAK) activated downstream of MAP3K5-p38 MAPK signaling, activates TP53 and contributes to cellular senescence (Sun et al. 2007).
primer:origin duplex with DNA
damageprimer:origin duplex with DNA
damageprimer:origin
duplexHere, transcriptional regulatory processes that mediate the SASP are annotated. DNA damage triggers ATM-mediated activation of TP53, resulting in the increased level of CDKN1A (p21). CDKN1A-mediated inhibition of CDK2 prevents phosphorylation and inactivation of the Cdh1:APC/C complex, allowing it to ubiquitinate and target for degradation EHMT1 and EHMT2 histone methyltransferases. As EHMT1 and EHMT2 methylate and silence the promoters of IL6 and IL8 genes, degradation of these methyltransferases relieves the inhibition of IL6 and IL8 transcription (Takahashi et al. 2012). In addition, oncogenic RAS signaling activates the CEBPB (C/EBP-beta) transcription factor (Nakajima et al. 1993, Lee et al. 2010), which binds promoters of IL6 and IL8 genes and stimulates their transcription (Kuilman et al. 2008, Lee et al. 2010). CEBPB also stimulates the transcription of CDKN2B (p15-INK4B), reinforcing the cell cycle arrest (Kuilman et al. 2008). CEBPB transcription factor has three isoforms, due to three alternative translation start sites. The CEBPB-1 isoform (C/EBP-beta-1) seems to be exclusively involved in growth arrest and senescence, while the CEBPB-2 (C/EBP-beta-2) isoform may promote cellular proliferation (Atwood and Sealy 2010 and 2011). IL6 signaling stimulates the transcription of CEBPB (Niehof et al. 2001), creating a positive feedback loop (Kuilman et al. 2009, Lee et al. 2010). NF-kappa-B transcription factor is also activated in senescence (Chien et al. 2011) through IL1 signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009). NF-kappa-B binds IL6 and IL8 promoters and cooperates with CEBPB transcription factor in the induction of IL6 and IL8 transcription (Matsusaka et al. 1993, Acosta et al. 2008). Besides IL6 and IL8, their receptors are also upregulated in senescence (Kuilman et al. 2008, Acosta et al. 2008) and IL6 and IL8 may be master regulators of the SASP.
IGFBP7 is also an SASP component that is upregulated in response to oncogenic RAS-RAF-MAPK signaling and oxidative stress, as its transcription is directly stimulated by the AP-1 (JUN:FOS) transcription factor. IGFBP7 negatively regulates RAS-RAF (BRAF)-MAPK signaling and is important for the establishment of senescence in melanocytes (Wajapeyee et al. 2008).
Please refer to Young and Narita 2009 for a recent review.
PTK6 activates STAT3-mediated transcription (Ikeda et al. 2009, Ikeda et al. 2010) and may also activate STAT5-mediated transcription (Ikeda et al. 2011). PTK6 promotes cell motility and migration by regulating the activity of RHO GTPases RAC1 (Chen et al. 2004) and RHOA (Shen et al. 2008), and possibly by affecting motility-related kinesins (Lukong and Richard 2008). PTK6 crosstalks with AKT1 (Zhang et al. 2005, Zheng et al. 2010) and RAS signaling cascades (Shen et al. 2008, Ono et al. 2014) and may be involved in MAPK7 (ERK5) activation (Ostrander et al. 2007, Zheng et al. 2012). PTK6 enhances EGFR signaling by inhibiting EGFR down-regulation (Kang et al. 2010, Li et al. 2012, Kang and Lee 2013). PTK6 may also enhance signaling by IGF1R (Fan et al. 2013) and ERBB3 (Kamalati et al. 2000).
PTK6 promotes cell cycle progression by phosphorylating and inactivating CDK inhibitor CDKN1B (p27) (Patel et al. 2015).
PTK6 activity is upregulated in osteopontin (OPN or SPP1)-mediated signaling, leading to increased VEGF expression via PTK6/NF-kappaB/ATF4 signaling path. PTK6 may therefore play a role in VEGF-dependent tumor angiogenesis (Chakraborty et al. 2008).
PTK6 binds and phosphorylates several nuclear RNA-binding proteins, including SAM68 family members (KHDRSB1, KHDRSB2 and KHDRSB3) (Derry et al. 2000, Haegebarth et al. 2004, Lukong et al. 2005) and SFPQ (PSF) (Lukong et al. 2009). The biological role of PTK6 in RNA processing is not known.
For a review of PTK6 function, please refer to Goel and Lukong 2015.
activity of SMAD2/SMAD3:SMAD4
heterotrimerAnnotated Interactions
pre-replicative
complex:CDC45:RPA1-4pre-replicative
complex:CDC45:RPA1-4pre-replicative
complex:CDC45:RPA1-4pre-replicative
complex:CDC45pre-replicative
complex:CDC45pre-replicative
complexpre-replicative
complexB:CDK1:ORC:origin
of replicationalpha:primase:DNA polymerase alpha:origin
complexepsilon:origin
complexepsilon:origin
complexpre-replicative
complexpre-replicative
complexThis reaction takes place in the 'nucleus' (Gambus et al. 2009, Remus et al. 2009, Chattopadhyay et al.2007, Fien et al. 2004).
Rb1 is normally hyperphosphorylated by CycD/CDK4/CDK6 and Cyclin E/CDK2 for transition into S-phase. PP2A can then reverse this reaction, in this case, in response to DNA damage induced checkpoint.
Transcription of the CDC25A gene can be directly activated by E2F1 (DeGregori et al. 1995, Vigo et al. 1999).
Transcription of the CDC25A gene is directly inhibited by the DREAM complex (Litovchick et al. 2007).
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus' and is mediated by the 'kinase activity' of 'DDK'.
This reaction takes place in the 'nucleoplasm'.
CDKN1A can be phosphorylated at tyrosine residue Y77 by protein tyrosine kinase ABL1 (Hukkelhoven et al. 2012). CDKN1B can be phosphorylated at tyrosine residue Y88, and probably also at the adjacent Y89, by protein tyrosine kinases ABL1 (Grimmler et al. 2007, James et al. 2008, Ray et al. 2009, Ou et al. 2011), LYN (Grimmler et al. 2007), SRC (Larrea et al. 2008), JAK2 (Jakel et al. 2011) and PTK6 (Patel et al. 2015). CDKN1C can be phosphorylated at tyrosine residue Y91 by protein tyrosine kinase ABL1 (Borriello et al. 2011).
Dislodgment of the tyrosine phosphorylated 3-10 helix of Cip/Kip CDK inhibitors from the active site of cyclin D-bound CDK4 or CDK6 results in increased catalytic activity of CDK4 or CDK6 by allowing ATP binding to the active site, but also by enabling activating phosphorylation of the T-loop of CDK4 or CDK6 phosphorylation by CDK7 in complex with cyclin H (Ray et al. 2009).
SRC-mediated phosphorylation of CDKN1B on tyrosine residue Y88 was shown to reduce protein stability of CDKN1B (Chu et al. 2007).
Without overexpression of BCR-ABL or SRC-family tyrosine kinases in several cell systems, tyrosine phosphorylated p27 is either undetectable or a very low abundance species (Ishida et al. 2000, Jaimes et al. 2008, Grimmler et al. 2007) that does not bind preferentially to CDK4 (Jaimes et al. 2008). Therefore, tyrosine phosphorylation of p27 is unlikely to be the sole explanation of the full activity of p27-bound CDK4:CCND complexes reported in previous studies (Blain et al. 1997, Coulonval et al. 2003, Bockstaele et al. 2006). It has been proposed that stoichiometry of the Cip/Kip complex with CDK4 or CDK6 and cyclin D, in addition to or alternative to tyrosine phosphorylation of Cip/Kip CDK inhibitors, determines their inhibitory role where binding of more than one molecule of CDKN1A, CDKN1B or CDKN1C would be needed to achieve inhibition of the CDK4/6:CCND complex (reviewed by Paternot et al. 2010).
In the absence of Cip/Kip proteins, a small number of CDK4/6:CCND complexes enter the nucleus through an unknown mechanism and phosphorylate target proteins (Bagui et al. 2003).
Phosphorylation of CDKN1A at serine residue S130 by CDK4/6 and CDK2 has been implicated as a pre-requisite for CAK-mediated phosphorylation of CDKN1A-bound CDK4 (Bisteau et al. 2013). Other kinases involved in phosphorylation of CDK4 at T172 remain to be defined (Bockstaele et al. 2009, Bisteau et al. 2013, reviewed by Paternot et al. 2010).
Transcription of the CDC6 gene is directly repressed by the DREAM complex (Litovchick et al. 2007).
The PCNA gene transcription is directly repressed by the DREAM complex (Litovchick et al. 2007).
primer:origin duplex with DNA
damageprimer:origin duplex with DNA
damageprimer:origin duplex with DNA
damageprimer:origin duplex with DNA
damageprimer:origin
duplex