Gene interactions and pathways from curated databases and text-mining

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CDKN2A — TP53

Pathways - manually collected, often from reviews:

  • OpenBEL Selventa BEL large corpus: TP53 → Complex of CDKN2A-MDM2 (increases, CDKN2A/MDM2 Activity)
    Evidence: CTCF induces expression of the gene encoding p19Arf, which sequesters the p53 inhibitor MDM2, resulting in activation of p53

Protein-Protein interactions - manually collected from original source literature:

Studies that report less than 10 interactions are marked with *

Text-mined interactions from Literome

Kurokawa et al., Oncogene 1999 : Induction of p19ARF activated p53 by increasing its stability, and allowed the expression of p21Cip1, which bound to all of the cyclin D1-cdk complexes ( cyclin D1-cdk2, -cdk4, and -cdk6 ) thereby inhibiting their kinase activities
Tao et al., Proc Natl Acad Sci U S A 1999 : Taken together, p19(ARF) could stabilize p53 by inhibiting the nuclear export of Mdm2
Xing et al., Clin Cancer Res 1999 (Carcinoma, Squamous Cell...) : It was shown that p14ARF and p16INK4a play active roles in the p53 and Rb tumor suppressive pathways, respectively, and p15INK4b is a mediator of the extracellular growth inhibition signals
Khan et al., Proc Natl Acad Sci U S A 2000 (Polyploidy) : We used p19ARF knockout mouse embryo fibroblasts to show that DNA damage and microtubule disruption require p19ARF to induce p53 responses, whereas ribonucleotide depletion and inhibition of RNA synthesis by low doses of actinomycin D do not
Ueda et al., Nihon rinsho. Japanese journal of clinical medicine 2000 (Dysplastic Nevus Syndrome...) : p16 gene locus also codes for p14ARF and acts as tumor suppressor through activation of Rb by p16 and p53 by p14ARF
Sano et al., Pathol Int 2000 (Carcinoma, Squamous Cell...) : A physical association between p14ARF and MDM2 blocks MDM2 induced p53 degradation, resulting in increased levels of p53 , which in turn leads to cell cycle arrest
Weitzman et al., Mol Cell 2000 (Hepatitis, Animal) : Primary fibroblasts lacking JunD displayed p53 dependent growth arrest, upregulated p19(Arf) expression, and premature senescence
Querido et al., J Virol 2001 : Degradation of p53 was independent of both MDM2 and p19ARF , regulators of p53 stability in mammalian cells, but required an extended region of E4orf6 from residues 44 to 274, which appeared to possess three separate biological functions
Raveh et al., Nat Cell Biol 2001 (Cell Transformation, Neoplastic) : Ectopic expression of DAP kinase suppressed oncogenic transformation of primary embryonic fibroblasts by activating p53 in a p19ARF dependent manner
Roper et al., EMBO Rep 2001 (MAP Kinase Signaling System) : Thus, p19ARF is not essential for Raf induced p53 induction and cell cycle arrest in keratinocytes, indicating that oncogenes engage p53 activity via multiple mechanisms
Esteller et al., Cancer Res 2001 : Because it is known that p14ARF prevents MDM2 nucleocytoplasmic shuttling and thus stabilizes p53 by attenuating MDM2 mediated degradation, we studied the relationship of p14ARF epigenetic silencing to the expression and localization of MDM2 and p53
Lin et al., Proc Natl Acad Sci U S A 2001 (Carcinoma, Squamous Cell...) : This result suggests that p19(ARF) can activate p53 without overtly affecting Mdm2 subcellular localization
Ho et al., Breast Cancer Res Treat 2001 (Breast Neoplasms...) : p14ARF , an alternate transcript of the INK4A tumor suppressor locus, prevents hdm2 induced transcriptional silencing of p53 by binding hdm2
Rizos et al., Oncogene 2001 (Genetic Predisposition to Disease...) : This mutant p14ARF , 60ins16, was restricted to the cytoplasm, did not stabilize p53 and was unable to arrest the growth of a p53 expressing melanoma cell line
Piboonniyom et al., Oral Oncol 2002 (Carcinoma, Squamous Cell...) : This locus encodes two partially overlapping genes, the cdk inhibitor p16(ink4a) , and p14(ARF), an inhibitor of mdm2 mediated degradation of p53
Ferbeyre et al., Mol Cell Biol 2002 (MAP Kinase Signaling System) : Although the levels of exogenous p53 achieved in ARF-null cells were relatively low, the stabilizing effects of p19(ARF) on p53 could not explain the cooperation between oncogenic Ras and p53 in promoting senescence
Tsuji et al., Biochem Biophys Res Commun 2002 : By inactivating Mdm2, p19(ARF) upregulates p53 activities to induce cell cycle arrest and sensitize cells to apoptosis in the presence of collateral signals
Rogoff et al., Mol Cell Biol 2002 : We find that although p19ARF contributes to p53 accumulation in response to E2F expression, p19ARF is not required for E2F1 mediated apoptosis
Kuo et al., Cancer Res 2003 : p19(Arf) induces growth arrest by antagonizing the activity of the p53 negative regulator, Mdm2, thereby inducing a p53 transcriptional response
Zhu et al., Chin J Cancer 2003 : When expression of p53 elevated, p53-mdm2 and p14(ARF)-mdm2 feedback loops can accurately regulate the expression level of p53 , and the cooperation of p33ING1b gene is also needed in the process of p53 exerting normal function
Zhang et al., Chin Med J (Engl) 2003 (Pancreatic Neoplasms) : Western blotting showed p14ARF upregulates p53 expression
Xia et al., Cancer Res 2004 (Breast Neoplasms) : In summary, these results demonstrate that up-regulation of p14ARF paralleled with MDM2 inhibition contributes to p53 accumulation in the nucleus and causes a high responsiveness of p53 in chronic IR-treated breast cancer cells
Jackson et al., Oncogene 2004 (Bone Neoplasms...) : We conclude that the phosphorylation of p53 on N-terminal serine residues is not required for increased transcription of the great majority of p53-responsive genes and that the induction of p53 by p14ARF , with little phosphorylation, leads to substantial repression of genes whose products have roles in proliferation
Li et al., Oncogene 2004 (Ataxia Telangiectasia) : P14/p19ARF ( ARF ) plays a major role in the activation of p53 by oncogenic signals ... We report here that forced expression of p14ARF enhances phosphorylation of p53 serine 15 (p53S15) in NIH3T3, IMR90 and MCF7 cells
Kuo et al., Genes Dev 2004 : Although p19Arf binds to the Mdm2 E3 ubiquitin protein ligase to activate p53 , neither of these molecules regulates p19Arf turnover
Kelly-Spratt et al., PLoS Biol 2004 (Carcinoma, Squamous Cell...) : Ectopic expression of oncogenes such as Ras induces expression of p19(Arf) , which, in turn, activates p53 and growth arrest
Vestey et al., Breast Cancer Res 2004 (Breast Neoplasms...) : p14ARF is negatively regulated by p53 and through p53 independent pathways
Lozano et al., J Pathol 2005 (Disease Models, Animal...) : Additionally, upstream regulators of p53 activity, such as p19(Arf) and Atm, are themselves critical tumour modifiers/suppressors
Tanaka et al., Nephron. Physiology 2005 (Acute Kidney Injury...) : We also examined the effect of p19(ARF) overexpression on p53 levels and cell cycle progression in MDCK cells
Silva et al., EMBO J 2005 : In cultured cells, p19Arf decreased Pdgfrbeta and blocked Pdgf-B-driven proliferation independently of Mdm2 and p53
Warburton et al., Cancer Res 2005 (Carcinoma, Renal Cell...) : We have found that p53 is functional in p53 wild-type renal cell carcinoma cells and that this activity is significantly regulated by MDM2 and to a much lesser extent by p14ARF
Balsitis et al., J Virol 2005 (Hyperplasia...) : While E7-mediated p21 induction was partially p53 dependent, neither p53 nor p21 induction by E7 required p19(ARF)
Castillo et al., J Virol 2005 : We present here evidence suggesting that IE1-72 may activate the p53 pathway by increasing the levels of p19(Arf) and by inducing the phosphorylation of p53 at Ser15
Ruiz et al., Cell cycle (Georgetown, Tex.) 2006 (Carcinoma, Squamous Cell...) : In particular, we characterized the aberrant p53 activation mediated by E2F/p19(ARF) and other transduction pathways
Zeini et al., J Immunol 2006 : This up-regulation of p19(ARF) activates p53 , leading to apoptosis
Lara et al., Mol Carcinog 2007 (Carcinoma, Squamous Cell...) : Detailed biochemical analyses have indicated that, in the absence of pRb, multiple pathways, including the aberrant p53 activation mediated by E2F/p19(ARF) , are activated leading to increased tumor apoptosis
Rizos et al., Cell cycle (Georgetown, Tex.) 2007 (Genetic Predisposition to Disease) : p14ARF regulates E2F-1 ubiquitination and degradation via a p53 dependent mechanism
Mascaux et al., Eur Respir J 2008 (Bronchial Neoplasms...) : Murine double minute clone 2 (MDM2), p14 alternate reading frame (p14arf) , and nucleophosmin (NPM) regulate p53 activity
Leong et al., Mol Cancer Res 2009 : p53 Deficiency leads to compensatory up-regulation of p16INK4a ... Here, we report that p53 controls p16(INK4a) expression in a unique way ... p53 deficiency led to up-regulation of p16(INK4a) in primary mouse embryonic fibroblasts, osteoblasts, and various mouse organs, and an increase in the p16(INK4a) promoter activity, without affecting the half-life of p16(INK4a) ... Reconstitution of p53, but not mutant p53 , restored the proper expression of p16(INK4a) ... p53 did not repress the p16(INK4a) promoter activity either
Huschtscha et al., J Cell Sci 2009 : Exogenous p16(INK4a) expression decreased levels of both p53 transcript and protein, and this effect was inhibited by nutlin-3a, indicating that p16(INK4a) can regulate p53 expression by affecting both p53 transcription and Mdm2 dependent degradation of p53
Kashuba et al., Int J Cancer 2011 (Breast Neoplasms) : This resembles the effect of p14ARF on p53
Kawagishi et al., Cancer Res 2010 (Cell Transformation, Neoplastic...) : Translational repression of VEGFA mRNA by p19(ARF) does not require p53 , a major target of the ARF tumor suppressor pathway, but instead correlates with binding to nucleophosmin/B23
Macias et al., Cancer Cell 2010 : Furthermore, ribosomal perturbation induced p53 response does not require tumor suppressor p19ARF
Xie et al., Zhongguo Fei Ai Za Zhi 2006 : Both p16INK4a and p14ARF are cell cycle regulatory proteins and play an important role in Rb and p53 passways respectively
Chien et al., Oncogene 2011 : Here, we report that, in two p16 ( -/- ), pRb ( WT ) and p53 ( WT ) cell lines ( MCF7 and U87 ), p16(INK4a) overexpression induces a dramatic decrease in CDK1 protein expression
Nakamura et al., Mol Cell Biol 2011 : In the absence of Hzf and HuR, p53 induction by p19(ARF) is significantly attenuated, and the cells consequently acquire resistance to p19(ARF)
Nishizawa et al., Cancer Sci 2012 : Bach1 mediated suppression of p53 is inhibited by p19(ARF) independently of MDM2
Widau et al., Mol Cell Biol 2012 : Although p19(Arf) controls Pdgfrß mRNA in a p53 dependent manner, it also blunts Pdgfrß protein expression by blocking new protein synthesis in the absence of p53
Yamada et al., Mol Cell 2013 : p14ARF activates p53 by binding and inhibiting HDM2, resulting, inter alia, in increased transcription and expression of the cyclin dependent kinase inhibitor p21 and consequent cell-cycle arrest
Nichols et al., Case reports in oncological medicine 2013 : The primary tumor and blood underwent exome sequencing which revealed deletions in CDKN2A as well as PPP1R13B, which induces p53
Parker et al., DNA Cell Biol 1994 (Melanoma...) : The variation of p53 in association with mts1 gene expression suggests that the mts1 product might interact with and stabilize p53