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
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 .
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