Pathway Map Details

Transcription_P53 signaling pathway

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Object list (links open in MetaCore):

p14ARF, p21, MAP4, beta-Catenin, MEK4(MAP2K4), C-FOS, P300, MKP-7, MDM2, APEX, PIAS2, MKP-1, p53, XPA, ATR, FHL2, CDK2, TDG, CBP, Bcl-2, PCAF, MMP-2, PIAS1, Core complex of TFIIH, MTA2, VEGFR-2, XPC, Histone deacetylase class I, E2F1, VEGFR-1, SUMO-1, NF-KB, MEKK1(MAP3K1), JNK(MAPK8-10), ATM, HSP27, RanBP2, VEGF-A, Rb protein


p 53 signaling pathway

The Tumor protein p53 ( p53 ) plays a critical role in safeguarding the integrity of the genome. Upon activation, p53 binds to the enhancer/promoter elements of downstream target genes and regulates their transcription, through which it initiates cellular programs that account for most of its tumor-suppressor functions [1].

The signal transduction circuit of p53 consists of the upstream mediators, the core regulation components and the downstream effectors.

The core regulatory circuitry consists of Mdm2 p53 binding protein homolog ( MDM2 ), Cyclin-dependent kinase inhibitor 2A ( p14ARF ) and E2F transcription factor 1 ( E2F1 ). p53 activates MDM2 transcription [1]. MDM2 in conjunction with Proteasome 26S subunit non-ATPase 10 (( PSMD10 (Gankyrin) ) mediates p53 ubiquitination and degradation [1], [2]. E2F1 activates transcription of p53 and p14ARF. p14ARF facilitates proteolytic degradation of E2F1 and MDM2 -mediated p53 ubiquitination [3], [1]. Transcription of p53 is also mediated by nuclear factor kappaB ( NF-KB ) in a response to stress [4].

MDM2 is regulated by sumoylation during nuclear translocation by RAN binding protein 2 ( RanBP2 ) and then further sumoylated in the nucleus by protein inhibitor of activated STAT 1 and 2 ( PIAS1 and PIAS2 ) [5]. MDM2 is a subject for self-ubiquitination. Ubiquitination leads to impairment of MDM2 ubiquitin activity for p53. Association of MDM2 with SMT3 suppressor of mif two 3 homolog 1 ( SUMO-1 ) protects MDM2 from ubiquitination. This increase ubiquitination and degradation of p53 [6]. Retinoblastoma 1 ( Rb protein ) binds to MDM2 and inhibits its activity in PSMD10 - dependent manner resulting in stabilization of p53 [2]. P53 in turn is able to transcriptionally activate Rb protein [7]. Also, Rb protein participates in p53 -mediated regulation of G2 checkpoint [8].

E1A binding protein p300 ( p300 ), CREB binding protein ( CBP ) and K(lysine) acetyltransferase 2B ( PCAF ) regulate p53 transcriprional activity via acetylation. p300 and CBP -dependent acethylation and stabilization of p53 is important after DNA damage. Also, p300 indirectly participates in p53 degradation. Possibly it plays a scaffolding role in p53 ubiquitination by bringing together the p53 ubiquitination target and the MDM2 in unstressed, cycling cells [9], [10]. MDM2 in this case also inhibits p300 acethylation of p53 [11]. The deacetylation of p53 is mediated by the Histone deacetylase class I complex, Deacetylation results in the repression p53 -dependent transcriptional activation [12].

P53 is phosphorylated by Ataxia telangiectasia mutated ( ATM ) in response to DNA damage [13]. Also, Mitogen-activated protein ( JNK(MAPK8-10) ) associates with p53 and phosphorylates it [14], [15]. Phosphorylation of p53 activates p53 through three mechanisms: stabilizing it by disrupting p53 - Mdm2 interaction; regulating p53 transactivation activity; promoting p53 nuclear localization [1]. Interaction of p53 with APEX nuclease ( APEX ) leads to the activation of p53 that possibly does not require covalent modification of the p53 protein [16].

P53 regulates expression of numerous genes. P53 activates expression of Matrix metallopeptidase 2 ( MMP-2 ) [17], Heat shock 27kDa protein 2 ( HSP27 ) [18], Four and a half LIM domains 2 ( FHL2 ) [19], a known Coactivator of beta-Catenin [20]. The p53 is an important mediator of the cellular response to ultraviolet-irradiation induced DNA damage and affects the efficiency of the nucleotide excision repair pathway via regulation of Xeroderma pigmentosum, complementation group C ( XPC ) expression, which is involved in DNA damage recognition [21], [22]. P53 regulates expression of V-fos FBJ murine osteosarcoma viral oncogene homolog ( C-FOS ) [23], [24]. Inhibition of Microtubule-associated protein 4 ( MAP4 ) can reduce microtubule polymerization [25].


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