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 .
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 . MDM2 in conjunction with Proteasome 26S subunit non-ATPase 10 (( PSMD10 (Gankyrin) ) mediates p53 ubiquitination and degradation , . E2F1 activates transcription of p53 and p14ARF. p14ARF facilitates proteolytic degradation of E2F1 and MDM2 -mediated p53 ubiquitination , . Transcription of p53 is also mediated by nuclear factor kappaB ( NF-KB ) in a response to stress .
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 ) . 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 . Retinoblastoma 1 ( Rb protein ) binds to MDM2 and inhibits its activity in PSMD10 - dependent manner resulting in stabilization of p53 . P53 in turn is able to transcriptionally activate Rb protein . Also, Rb protein participates in p53 -mediated regulation of G2 checkpoint .
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 , . MDM2 in this case also inhibits p300 acethylation of p53 . The deacetylation of p53 is mediated by the Histone deacetylase class I complex, Deacetylation results in the repression p53 -dependent transcriptional activation .
P53 is phosphorylated by Ataxia telangiectasia mutated ( ATM ) in response to DNA damage . Also, Mitogen-activated protein ( JNK(MAPK8-10) ) associates with p53 and phosphorylates it , . Phosphorylation of p53 activates p53 through three mechanisms: stabilizing it by disrupting p53 - Mdm2 interaction; regulating p53 transactivation activity; promoting p53 nuclear localization . Interaction of p53 with APEX nuclease ( APEX ) leads to the activation of p53 that possibly does not require covalent modification of the p53 protein .
P53 regulates expression of numerous genes. P53 activates expression of Matrix metallopeptidase 2 ( MMP-2 ) , Heat shock 27kDa protein 2 ( HSP27 ) , Four and a half LIM domains 2 ( FHL2 ) , a known Coactivator of beta-Catenin . 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 , . P53 regulates expression of V-fos FBJ murine osteosarcoma viral oncogene homolog ( C-FOS ) , . Inhibition of Microtubule-associated protein 4 ( MAP4 ) can reduce microtubule polymerization .