Search results for E2F4

Showing 21 results out of 66

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Types

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Protein (1 results from a total of 1)

Identifier: R-HSA-68664
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: E2F4: Q16254

Reaction (6 results from a total of 30)

Identifier: R-HSA-6798282
Species: Homo sapiens
Compartment: nucleoplasm
The promoter of the CDC25C gene contains p53 response elements as well as E2F binding sites and can bind both TP53 (St Clair et al. 2004) and E2F4 (Benson et al. 2014). E2F4 transcription repressor complex consists of E2F4, a transcriptional co-factor TFDP1 (DP1) or TFDP2 (DP2), and a retinoblastoma family protein RBL1 (p107) or RBL2 (p130). The CDK inhibitor p21 (CDKN1A), induced by TP53, positively affects E2F4 recruitment to the CDC25C promoter, probably by upregulating RBL2 (Helmbold et al. 2009, Benson et al. 2014).
Identifier: R-HSA-6798268
Species: Homo sapiens
Compartment: nucleoplasm
Binding of TP53 and the E2F4 repressor complex to the promoter of the CDC25C gene results in the inhibition of CDC25C transcription, an important step in the maintenance of the G2 cell cycle checkpoint (St. Clair et al. 2004, Benson et al. 2014).
Identifier: R-HSA-8964567
Species: Homo sapiens
Compartment: nucleoplasm
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).
Identifier: R-HSA-8964550
Species: Homo sapiens
Compartment: nucleoplasm
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).
Identifier: R-HSA-8964580
Species: Homo sapiens
Compartment: nucleoplasm
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).
Identifier: R-HSA-8964561
Species: Homo sapiens
Compartment: nucleoplasm
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).

Set (2 results from a total of 2)

Identifier: R-HSA-1226069
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-8964549
Species: Homo sapiens
Compartment: nucleoplasm

Complex (6 results from a total of 24)

Identifier: R-HSA-2127252
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-1362228
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-1226088
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-1226072
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-1226089
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-1227668
Species: Homo sapiens
Compartment: nucleoplasm

Pathway (6 results from a total of 9)

Identifier: R-HSA-1362277
Species: Homo sapiens
Compartment: nucleoplasm
DREAM complex is evolutionarily conserved and is reponsible for transcriptional repressession of cell cycle-regulated genes in G0 and early G1.
Identifier: R-HSA-2173793
Species: Homo sapiens
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).
Identifier: R-HSA-6804114
Species: Homo sapiens
TP53 contributes to the establishment of G2 arrest by inducing transcription of GADD45A and SFN, and by inhibiting transcription of CDC25C. TP53 induces GADD45A transcription in cooperation with chromatin modifying enzymes EP300, PRMT1 and CARM1 (An et al. 2004). GADD45A binds Aurora kinase A (AURKA), inhibiting its catalytic activity and preventing AURKA-mediated G2/M transition (Shao et al. 2006, Sanchez et al. 2010). GADD45A also forms a complex with PCNA. PCNA is involved in both normal and repair DNA synthesis. The effect of GADD45 interaction with PCNA, if any, on S phase progression, G2 arrest and DNA repair is not known (Smith et al. 1994, Hall et al. 1995, Sanchez et al. 2010, Kim et al. 2013). SFN (14-3-3-sigma) is induced by TP53 (Hermeking et al. 1997) and contributes to G2 arrest by binding to the complex of CDK1 and CCNB1 (cyclin B1) and preventing its translocation to the nucleus. Phosphorylation of a number of nuclear proteins by the complex of CDK1 and CCNB1 is needed for G2/M transition (Chan et al. 1999). While promoting G2 arrest, SFN can simultaneously inhibit apoptosis by binding to BAX and preventing its translocation to mitochondria, a step involved in cytochrome C release (Samuel et al. 2001). TP53 binds the promoter of the CDC25C gene in cooperation with the transcriptional repressor E2F4 and represses CDC25C transcription, thus maintaining G2 arrest (St Clair et al. 2004, Benson et al. 2014). The zinc finger transcription factor ZNF385A (HZF) is a direct transcriptional target of TP53 that can form a complex with TP53 and facilitate TP53-mediated induction of SFN transcription (Das et al. 2007).
Identifier: R-HSA-2173796
Species: Homo sapiens
After phosphorylated SMAD2 and/or SMAD3 form a heterotrimer with SMAD4, SMAD2/3:SMAD4 complex translocates to the nucleus (Xu et al. 2000, Kurisaki et al. 2001, Xiao et al. 2003). In the nucleus, linker regions of SMAD2 and SMAD3 within SMAD2/3:SMAD4 complex can be phosphorylated by CDK8 associated with cyclin C (CDK8:CCNC) or CDK9 associated with cyclin T (CDK9:CCNT). CDK8/CDK9-mediated phosphorylation of SMAD2/3 enhances transcriptional activity of SMAD2/3:SMAD4 complex, but also primes it for ubiquitination and consequent degradation (Alarcon et al. 2009).

The transfer of SMAD2/3:SMAD4 complex to the nucleus can be assisted by other proteins, such as WWTR1. In human embryonic cells, WWTR1 (TAZ) binds SMAD2/3:SMAD4 heterotrimer and mediates TGF-beta-dependent nuclear accumulation of SMAD2/3:SMAD4. The complex of WWTR1 and SMAD2/3:SMAD4 binds promoters of SMAD7 and SERPINE1 (PAI-1 i.e. plasminogen activator inhibitor 1) genes and stimulates their transcription (Varelas et al. 2008). Stimulation of SMAD7 transcription by SMAD2/3:SMAD4 represents a negative feedback loop in TGF-beta receptor signaling. SMAD7 can be downregulated by RNF111 ubiquitin ligase (Arkadia), which binds and ubiquitinates SMAD7, targeting it for degradation (Koinuma et al. 2003).

SMAD2/3:SMAD4 heterotrimer also binds the complex of RBL1 (p107), E2F4/5 and TFDP1/2 (DP1/2). The resulting complex binds MYC promoter and inhibits MYC transcription. Inhibition of MYC transcription contributes to anti-proliferative effect of TGF-beta (Chen et al. 2002). SMAD2/3:SMAD4 heterotrimer also associates with transcription factor SP1. SMAD2/3:SMAD4:SP1 complex stimulates transcription of a CDK inhibitor CDKN2B (p15-INK4B), also contributing to the anti-proliferative effect of TGF-beta (Feng et al. 2000).

MEN1 (menin), a transcription factor tumor suppressor mutated in a familial cancer syndrome multiple endocrine neoplasia type 1, forms a complex with SMAD2/3:SMAD4 heterotrimer, but transcriptional targets of SMAD2/3:SMAD4:MEN1 have not been elucidated (Kaji et al. 2001, Sowa et al. 2004, Canaff et al. 2012).

JUNB is also an established transcriptional target of SMAD2/3:SMAD4 complex (Wong et al. 1999).
Identifier: R-HSA-3304351
Species: Homo sapiens
Signaling by the TGF-beta receptor complex is tumor suppressive, as it inhibits cell growth and promotes cell differentiation and apoptosis (Shipley et al. 1986, Hannon et al. 1994, Datto et al. 1995, Chen et al. 2002, Azar et al. 2009). TGF-beta signaling is frequently impaired in cancer, mostly through SMAD4 gene deletion or loss-of-function mutations (described in the pathway Loss of Function of SMAD4 in Cancer), which are especially frequent in pancreatic cancer (Hahn et al. 1996, Shi et al. 1997, Fleming et al. 2013). Signaling by TGF-beta receptor complex can also be disrupted by loss-of-function mutations in SMAD2 and SMAD3 (Fleming et al. 2013), as described in the pathway Loss of Function of SMAD2/SMAD3 in Cancer, or loss-of-function mutations in TGFBR2 (TGF-beta receptor II) (Markowitz et al. 1995, Garrigue-Antar et al. 1995, Parsons et al. 1995, Grady et al. 1999), as described in the pathway Loss of Function of TGFBR2 in Cancer, or TGFBR1 (TGF-beta receptor I) (Chen et al. 1998, Chen et al. 2001, Goudie et al. 2011), as described in the pathway Loss of Function of TGFBR1 in Cancer.

In advanced cancer, signaling by TGF-beta may be tumor promoting, as it induces epithelial-to-mesenchymal transition (EMT), thereby increasing invasiveness (Cui et al. 1996, Guasch et al. 2007, reviewed by Heldin et al. 2012).
Identifier: R-HSA-6791312
Species: Homo sapiens
Under a variety of stress conditions, TP53 (p53), stabilized by stress-induced phosphorylation at least on S15 and S20 serine residues, can induce the transcription of genes involved in cell cycle arrest. Cell cycle arrest provides cells an opportunity to repair the damage before division, thus preventing the transmission of genetic errors to daughter cells. In addition, it allows cells to attempt a recovery from the damage and survive, preventing premature cell death.

TP53 controls transcription of genes involved in both G1 and G2 cell cycle arrest. The most prominent TP53 target involved in G1 arrest is the inhibitor of cyclin-dependent kinases CDKN1A (p21). CDKN1A is one of the earliest genes induced by TP53 (El-Deiry et al. 1993). CDKN1A binds and inactivates CDK2 in complex with cyclin A (CCNA) or E (CCNE), thus preventing G1/S transition (Harper et al. 1993). Nevertheless, under prolonged stress, the cell destiny may be diverted towards an apoptotic outcome. For instance, in case of an irreversible damage, TP53 can induce transcription of an RNA binding protein PCBP4, which can bind and destabilize CDKN1A mRNA, thus alleviating G1 arrest and directing the affected cell towards G2 arrest and, possibly, apoptosis (Zhu and Chen 2000, Scoumanne et al. 2011). Expression of E2F7 is directly induced by TP53. E2F7 contributes to G1 cell cycle arrest by repressing transcription of E2F1, a transcription factor that promotes expression of many genes needed for G1/S transition (Aksoy et al. 2012, Carvajal et al. 2012). ARID3A is a direct transcriptional target of TP53 (Ma et al. 2003) that may promote G1 arrest by cooperating with TP53 in induction of CDKN1A transcription (Lestari et al. 2012). However, ARID3A may also promote G1/S transition by stimulating transcriptional activity of E2F1 (Suzuki et al. 1998, Peeper et al. 2002).

TP53 contributes to the establishment of G2 arrest by inducing transcription of GADD45A and SFN, and by inhibiting transcription of CDC25C. TP53 induces GADD45A transcription in cooperation with chromatin modifying enzymes EP300, PRMT1 and CARM1 (An et al. 2004). GADD45A binds Aurora kinase A (AURKA), inhibiting its catalytic activity and preventing AURKA-mediated G2/M transition (Shao et al. 2006, Sanchez et al. 2010). GADD45A also forms a complex with PCNA. PCNA is involved in both normal and repair DNA synthesis. The effect of GADD45 interaction with PCNA, if any, on S phase progression, G2 arrest and DNA repair is not known (Smith et al. 1994, Hall et al. 1995, Sanchez et al. 2010, Kim et al. 2013). SFN (14-3-3-sigma) is induced by TP53 (Hermeking et al. 1997) and contributes to G2 arrest by binding to the complex of CDK1 and CCNB1 (cyclin B1) and preventing its translocation to the nucleus. Phosphorylation of a number of nuclear proteins by the complex of CDK1 and CCNB1 is needed for G2/M transition (Chan et al. 1999). While promoting G2 arrest, SFN can simultaneously inhibit apoptosis by binding to BAX and preventing its translocation to mitochondria, a step involved in cytochrome C release (Samuel et al. 2001). TP53 binds the promoter of the CDC25C gene in cooperation with the transcriptional repressor E2F4 and represses CDC25C transcription, thus maintaining G2 arrest (St Clair et al. 2004, Benson et al. 2014).

Several direct transcriptional targets of TP53 are involved in cell cycle arrest but their mechanism of action is still unknown. BTG2 is induced by TP53, leading to cessation of cellular proliferation (Rouault et al. 1996, Duriez et al. 2002). BTG2 binds to the CCR4-NOT complex and promotes mRNA deadenylation activity of this complex. Interaction between BTG2 and CCR4-NOT is needed for the antiproliferative activity of BTG2, but the underlying mechanism has not been elucidated (Rouault et al. 1998, Mauxion et al. 2008, Horiuchi et al. 2009, Doidge et al. 2012, Ezzeddine et al. 2012). Two polo-like kinases, PLK2 and PLK3, are direct transcriptional targets of TP53. TP53-mediated induction of PLK2 may be important for prevention of mitotic catastrophe after spindle damage (Burns et al. 2003). PLK2 is involved in the regulation of centrosome duplication through phosphorylation of centrosome-related proteins CENPJ (Chang et al. 2010) and NPM1 (Krause and Hoffmann 2010). PLK2 is frequently transcriptionally silenced through promoter methylation in B-cell malignancies (Syed et al. 2006). Induction of PLK3 transcription by TP53 (Jen and Cheung 2005) may be important for coordination of M phase events through PLK3-mediated nuclear accumulation of CDC25C (Bahassi et al. 2004). RGCC is induced by TP53 and implicated in cell cycle regulation, possibly through its association with PLK1 (Saigusa et al. 2007). PLAGL1 (ZAC1) is a zinc finger protein directly transcriptionally induced by TP53 (Rozenfeld-Granot et al. 2002). PLAGL1 expression is frequently lost in cancer (Varrault et al. 1998) and PLAGL1 has been implicated in both cell cycle arrest and apoptosis (Spengler et al. 1997), but its mechanism of action remains unknown.

The zinc finger transcription factor ZNF385A (HZF) is a direct transcriptional target of TP53 that can form a complex with TP53 and facilitate TP53-mediated induction of CDKN1A and SFN (14-3-3 sigma) transcription (Das et al. 2007).

For a review of the role of TP53 in cell cycle arrest and cell cycle transcriptional targets of TP53, please refer to Riley et al. 2008, Murray-Zmijewski et al. 2008, Bieging et al. 2014, Kruiswijk et al. 2015.

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