FOXO-mediated transcription of cell cycle genes (Homo sapiens)
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FOXO transcription factors induce expression of several genes that negatively regulate proliferation of different cell types, such as erythroid progenitors (Bakker et al. 2004, Wang et al. 2015) and neuroepithelial progenitor cells in the telencephalon (Seoane et al. 2004).
Transcription of cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip1) is directly stimulated by FOXO1, FOXO3 and FOXO4 (Seoane et al. 2004, Tinkum et al. 2013). FOXO transcription factors can cooperate with the SMAD2/3:SMAD4 complex to induce CDKN1A transcription in response to TGF-beta signaling (Seoane et al. 2004).
FOXO transcription factors FOXO1, FOXO3 and FOXO4 stimulate transcription of the CDKN1B (p27Kip1) gene, but direct binding of FOXOs to the CDKN1B gene locus has not been demonstrated (Dijkers et al. 2000, Medema et al. 2000, Lees et al. 2008).
FOXO3 and FOXO4, and possibly FOXO1, directly stimulate transcription of the GADD45A gene (Tran et al. 2002, Furukawa Hibi et al. 2002, Hughes et al. 2011, Sengupta et al. 2011, Ju et al. 2014).
Transcription of the retinoblastoma family protein RBL2 (p130), involved in the maintenance of quiescent (G0) state, is directly stimulated by FOXO1, FOXO3 and FOXO4 (Kops et al. 2002, Chen et al. 2006).
Transcription of the anti-proliferative protein CCNG2 is directly stimulated by FOXO1 and FOXO3, and possibly FOXO4 (Martinez Gac et al. 2004, Chen et al. 2006). Transcription of the anti-proliferative protein BTG1 is directly stimulated by FOXO3 (Bakker et al. 2004, Bakker et al. 2007, Wang et al. 2015).
Transcription of CAV1, encoding caveolin-1, involved in negative regulation of growth factor receptor signaling and establishment of quiescent cell phenotype, is directly stimulated by FOXO1 and FOXO3 (van den Heuvel et al. 2005, Roy et al. 2008, Nho et al. 2013, Sisci et al. 2013).
FOXO1 and FOXO3 promote transcription of the KLF4 gene, encoding a transcription factor Krueppel-like factor 4, which inhibits proliferation of mouse B cells (Yusuf et al. 2008).
FOXO1, together with the p-2S-SMAD2/3:SMAD4 complex, stimulates transcription of the MSTN gene, encoding myostatin, a TGF-beta family member that stimulates differentiation of myoblasts (Allen and Unterman 2007). View original pathway at Reactome.
Transcription of cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip1) is directly stimulated by FOXO1, FOXO3 and FOXO4 (Seoane et al. 2004, Tinkum et al. 2013). FOXO transcription factors can cooperate with the SMAD2/3:SMAD4 complex to induce CDKN1A transcription in response to TGF-beta signaling (Seoane et al. 2004).
FOXO transcription factors FOXO1, FOXO3 and FOXO4 stimulate transcription of the CDKN1B (p27Kip1) gene, but direct binding of FOXOs to the CDKN1B gene locus has not been demonstrated (Dijkers et al. 2000, Medema et al. 2000, Lees et al. 2008).
FOXO3 and FOXO4, and possibly FOXO1, directly stimulate transcription of the GADD45A gene (Tran et al. 2002, Furukawa Hibi et al. 2002, Hughes et al. 2011, Sengupta et al. 2011, Ju et al. 2014).
Transcription of the retinoblastoma family protein RBL2 (p130), involved in the maintenance of quiescent (G0) state, is directly stimulated by FOXO1, FOXO3 and FOXO4 (Kops et al. 2002, Chen et al. 2006).
Transcription of the anti-proliferative protein CCNG2 is directly stimulated by FOXO1 and FOXO3, and possibly FOXO4 (Martinez Gac et al. 2004, Chen et al. 2006). Transcription of the anti-proliferative protein BTG1 is directly stimulated by FOXO3 (Bakker et al. 2004, Bakker et al. 2007, Wang et al. 2015).
Transcription of CAV1, encoding caveolin-1, involved in negative regulation of growth factor receptor signaling and establishment of quiescent cell phenotype, is directly stimulated by FOXO1 and FOXO3 (van den Heuvel et al. 2005, Roy et al. 2008, Nho et al. 2013, Sisci et al. 2013).
FOXO1 and FOXO3 promote transcription of the KLF4 gene, encoding a transcription factor Krueppel-like factor 4, which inhibits proliferation of mouse B cells (Yusuf et al. 2008).
FOXO1, together with the p-2S-SMAD2/3:SMAD4 complex, stimulates transcription of the MSTN gene, encoding myostatin, a TGF-beta family member that stimulates differentiation of myoblasts (Allen and Unterman 2007). View original pathway at Reactome.
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TGF-beta Receptor
ComplexTGF beta (TGFB1) is secreted as a homodimer, and as such it binds to TGF beta receptor II (TGFBR2), inducing its dimerization. Binding of TGF beta enables TGFBR2 to form a stable hetero-tetrameric complex with TGF beta receptor I homodimer (TGFBR1). TGFBR2 acts as a serine/threonine kinase and phosphorylates serine and threonine residues within the short GS domain (glycine-serine rich domain) of TGFBR1.
The phosphorylated heterotetrameric TGF beta receptor complex (TGFBR) internalizes into clathrin coated endocytic vesicles where it associates with the endosomal membrane protein SARA. SARA facilitates the recruitment of cytosolic SMAD2 and SMAD3, which act as R-SMADs for TGF beta receptor complex. TGFBR1 phosphorylates recruited SMAD2 and SMAD3, inducing a conformational change that promotes formation of R-SMAD trimers and dissociation of R-SMADs from the TGF beta receptor complex.
In the cytosol, phosphorylated SMAD2 and SMAD3 associate with SMAD4 (known as Co-SMAD), forming a heterotrimer which is more stable than the R-SMAD homotrimers. R-SMAD:Co-SMAD heterotrimer translocates to the nucleus where it directly binds DNA and, in cooperation with other transcription factors, regulates expression of genes involved in cell differentiation, in a context-dependent manner.
The intracellular level of SMAD2 and SMAD3 is regulated by SMURF ubiquitin ligases, which target R-SMADs for degradation. In addition, nuclear R-SMAD:Co-SMAD heterotrimer stimulates transcription of inhibitory SMADs (I-SMADs), forming a negative feedback loop. I-SMADs bind the phosphorylated TGF beta receptor complexes on caveolin coated vesicles, derived from the lipid rafts, and recruit SMURF ubiquitin ligases to TGF beta receptors, leading to ubiquitination and degradation of TGFBR1. Nuclear R-SMAD:Co-SMAD heterotrimers are targets of nuclear ubiquitin ligases which ubiquitinate SMAD2/3 and SMAD4, causing heterotrimer dissociation, translocation of ubiquitinated SMADs to the cytosol and their proteasome-mediated degradation. For a recent review of TGF-beta receptor signaling, please refer to Kang et al. 2009.
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