Transcription - P53 signaling pathway

p53 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 [1], [3]. 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].

References:

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