DEFINITION
p53 is a transcription factor which in humans is encoded by the TP53 gene. Kegg Pathway
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
High
- Arginine
- E/Q = high O2
- S/G = high methylation potential
- Proline = high collagen? low DNA synthesis?
Low
- glutamine = low nucleotide bases synthesis
- Trp = low MMP
Similarities with other Tumor Suppressor Genes
High
- E/Q = high O2
- Asp/Asn = low proliferation ?
- Proline = high collagen? low DNA synthesis?
Both are degraded via ubiquitination
SYNTHESIS AND TURNOVER
mRNA synthesis
protein synthesis
post-translational modifications
- Under oxidative stress, the activity of p53 is governed by S-glutathionylation (Figure 2). This is when GSHadducts inhibit p53 on the Cys residues in the proximal DNA-binding domain (90). In stress, most posttranslational modifications on p53 enhance its transcriptional activity, which, in turn, triggers the cell cycle checkpoints.
S-glutathionylation on Cys141 of p53 interferes with p53 dimerisation, which inhibits p53 to DNA binding and
interferes with its main tumour suppressing function but also with its inhibition of angiogenesis, its role in apoptosis, and genomic stability.
p53+and+S-glutathionylation
isoleucin and p53
degradation
The mitochondrial p53 pathway. 2006
Both have
- high E/Q = high O2
- low glutamine = low nucleotide bases synthesis
only p53 has
- high Proline = high collagen? low DNA synthesis?
- higher S/G = higher methylation potential
the total sum of glut+gln+pro is the same in both proteins (around 21%). As ribonucleotide reductase requires iron a lack of iron will shift NADPH and Glu use in the direction of proline synthesis.
p53 iron deficiency
Iron-dependent regulation of MDM2 influences p53 activity and hepatic carcinogenesis. 2009
- Iron dependent regulation of MDM2/p53 was confirmed ex-vivo in human monocytes, by manipulation of iron pool and in a genetic model of iron deficiency, leading to modulation of p53 target genes involved in the antioxidant response and apoptosis.
- Gene expression analysis in immortalized mouse hepatocytes exposed to iron or the iron chelator deferoxamine revealed that iron downregulated, whereas deferoxamine upregulated, mRNA levels of mouse double minute gene 2 (MDM2), the ubiquitin ligase involved in the degradation of the oncosuppressor p53.
- Iron status influenced p53 ubiquitination and degradation rate, and the MDM2 inhibitor nutlin increased p53 levels in iron-depleted cells. A direct correlation exists between iron and p53.
Effect of iron status on the MDM2/p53 pathway in human monocytes. A: Effect of iron status on p53 protein levels. Twenty-four hours after plating, after removal of lymphocytes, cells were treated as indicated for 24 hours. Ct: control, untreated monocytes. H2O2 is shown as positive control. β-actin is shown as a loading control. AU (arbitrary units): indicates the p53/β-actin ratio as detected by densitometry. Results are representative of two independent experiments. B: Expression of mRNAs of transferrin receptor-1 (up-regulated by iron depletion), MDM2, p53, and p53 target genes (including Bax, Aldh4a1, Sod2) in monocytes of subjects with C282Y / HH (n = 6, black bars), and subjects with normal iron parameters negative for HFE mutations (n = 6, white bars). *P < 0.05 vs. control subjects. AU: mRNA levels, arbitrary units. C: MDM2 and p53 protein expression, as detected by Western blotting, in subjects with C282Y / HH, and in subjects with normal iron parameters negative for HFE mutations. Three representative subjects are shown for each group. β-actin is shown as a loading control.
Iron deprivation results in an increase in p53 expression. 1995
Deferoxamine (DFO)-induced iron deprivation caused an increase in p53 expression in ML-1 and Raji cells.
CELLULAR FUNCTIONS
p53 is one of the most mutated tumor suppressors in human cancers and as such has been intensively studied for a long time.
p53 is a major orchestrator of the cellular response to a broad array of stress types by regulating apoptosis, cell cycle arrest, senescence, DNA repair and genetic stability.
These effects are mediated by different mechanisms:
- transcription factor, and numerous p53 target genes have been identified.
- transcription-independent proapoptotic function mediated by the cytoplasmic pool of p53 that participates directly in the intrinsic apoptosis pathway by interacting with the multidomain members of the Bcl-2 family to induce mitochondrial outer membrane permeabilization.
cellular localization
Manganese superoxide dismutase vs. p53: Regulation of mitochondrial ROS, 2010
biological function
the p53 pathway site
Peng Jiang p53
p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. 2011
Less G6PD --> NADPH --> Deoxyribonucleotides --> DNA --> cell proliferation
a similar effect on G6PD is exerted by DHEA
The Role of p53 in Apoptosis, 2010
Recent studies have provided relevant and unprecedented information about mechanistic antiapoptotic functions of the endogenous bile acid, ursodeoxycholic acid (UDCA), suggesting that the finely tuned, complex control of p53 by Mdm-2 (mouse double minute-2, an oncoprotein) is a key step in UDCA modulation of p53-triggered apoptosis. We will also review recent therapeutic strategies and clinical applications of targeted agents, their safety, and efficacy, with particular emphasis on potential benefits of UDCA.
HMG-CoA+reductase+and+p53
REGULATION
IFI16
DIAGNOSTIC USE
