Transcription P53 signaling pathway
p 53 signaling pathway
The Tumor protein p53 ( p53 ) plays a critical role in safeguarding theintegrity of the genome. Upon activation, p53 binds to the enhancer/promoterelements of downstream target genes and regulates their transcription, through which itinitiates cellular programs that account for most of its tumor-suppressor functions[1].
The signal transduction circuit of p53 consists of the upstream mediators, thecore 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 E2Ftranscription 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 andp14ARF. p14ARF facilitates proteolytic degradation of E2F1 andMDM2 -mediated p53 ubiquitination [3], [1].Transcription of p53 is also mediated by nuclear factor kappaB ( NF-KB ) ina 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 ofactivated STAT 1 and 2 ( PIAS1 and PIAS2 ) [5]. MDM2 isa subject for self-ubiquitination. Ubiquitination leads to impairment of MDM2ubiquitin activity for p53. Association of MDM2 with SMT3 suppressor ofmif two 3 homolog 1 ( SUMO-1 ) protects MDM2 from ubiquitination. Thisincrease 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 inturn is able to transcriptionally activate Rb protein [7]. Also, Rbprotein participates in p53 -mediated regulation of G2 checkpoint [8].
E1A binding protein p300 ( p300 ), CREB binding protein ( CBP ) andK(lysine) acetyltransferase 2B ( PCAF ) regulate p53 transcriprionalactivity via acetylation. p300 and CBP -dependent acethylation andstabilization of p53 is important after DNA damage. Also, p300 indirectlyparticipates in p53 degradation. Possibly it plays a scaffolding role inp53 ubiquitination by bringing together the p53 ubiquitination target andthe 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 deacetylaseclass I complex, Deacetylation results in the repression p53 -dependenttranscriptional activation [12].
P53 is phosphorylated by Ataxia telangiectasia mutated ( ATM ) inresponse 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 threemechanisms: stabilizing it by disrupting p53 - Mdm2 interaction;regulating p53 transactivation activity; promoting p53 nuclear localization[1]. Interaction of p53 with APEX nuclease ( APEX ) leads tothe activation of p53 that possibly does not require covalent modification of thep53 protein [16].
P53 regulates expression of numerous genes. P53 activates expression ofMatrix 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 isan important mediator of the cellular response to ultraviolet-irradiation induced DNAdamage and affects the efficiency of the nucleotide excision repair pathway viaregulation 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-associatedprotein 4 ( MAP4 ) can reduce microtubule polymerization [25].
Map Key
