P53 Signaling Pathway

The transcription factor p53 plays a key part in the cell cycle and is the most important tumor suppressor. Upon cellular stress signals, such as DNA damage or oncogenic stress, p53 is activated by a cascade of phosphorylation events and other posttranslational modifications (PTMs), leading to the expression of p53 target genes involved in DNA repair, cell-cycle arrest, or apoptosis, if the damage is irreparable (Figure 1). The p53 target genes also have important roles in angiogenesis, senescence, and autophagy, connecting, for example, p53 and mammalian target of rapamycin (mTOR) signaling. For years, countless studies on p53 have increasingly revealed the connectivity and complexity of the p53 pathway, which extends to roles in metabolic regulation, development, and stem cell biology.

P53 Signaling Pathway Figure 1. The p53 pathway.

Cellular p53 protein levels in vertebrates are under the strict control of its negative regulators MDM2 and MDM4 (also known as MDMX). MDM2 is a transcriptional target of p53 and acts as an E3 ubiquitin ligase, which, together with its homolog MDMX, ubiquitinates p53, leading to nuclear export and proteasomal degradation of p53. MDMX itself has no intrinsic ubiquitin ligase activity, but it modulates MDM2 ubiquitination activity by the formation of heterodimers, thus also preventing MDM2 autoubiquitination. It also inhibits p53 directly, through binding to its transactivation domain. The p53 protein is such a powerful tumor suppressor that it is inactivated in almost every tumor, through either mutations in the TP53 gene or deregulation of its associated pathways. Therefore, understanding the structure of p53 and the molecular basis of its associated signaling pathways, and how they are deregulated in different cancer cell lines, is paramount for developing targeted anticancer strategies.

The tumor suppressor p53 plays crucial roles in cancer pathogenesis and therapy resistance and, therefore, represents a vital cellular drug target. Of note, p53 is inactivated in 50% of human cancers, and components of the p53 signaling pathway, such as p14Arf and Mdm2, are often misappropriated in the other 50% of cases. Furthermore, molecular epidemiological analyses revealed that several cancers, including breast, liver, head and neck, and hematopoietic malignancies, showed a significant association of TP53 mutations with worsened patient survival. Based on the paramount importance of p53 for tumorigenesis, several strategies have been developed to restore p53-instigated cell cycle-inhibitory, pro-apoptotic, and pro-senescence functions in p53 mutant cells and tumors. These have employed gene therapy methodologies using adenoviral p53 expression vectors, or small-molecule-/peptide-based methods to functionally reactivate mutant p53, and to block molecular targeting of p53 through chaperone and ubiquitin ligases to prevent its proteasomal degradation.

Great strides have been made in p53 drug discovery in recent years. So far, inhibiting the interaction of p53 with its negative regulators MDMX and MDM2 has proven to be the most successful, with several inhibitors from both academia and industry currently in clinical trials. Systematic functional and structural characterization of the p53 pathway and its interaction network is probably to reveal novel methods and drug targets. Analyses of p53 status and aberrant expression patterns in different cancer patients will then provide the platform for developing the personalized anticancer therapy to complement conventional treatment approaches. Creative Biogene is able to offer a variety of p53 signaling pathway related products including stable cell lines, viral particles and clones for your drug discovery projects.

P53 Signaling Pathway Product Panel

APAF1	BAX	CASP3	CASP8	CCNB1	CCND1
CCND3	CDK2	CDK6	CDKN1A	CDKN2A	CHEK2
FAS	GADD45A	GADD45B	MDM2	PPM1D	PTEN
RFWD2	RRM2B	SERPINB5	SFN	THBS1	TNFRSF10B
TP53	TSC2	ZMAT3	CASP8	CCND1	PTEN
RRM2B	CASP8	CCNB1	CCND1	CDKN1A	RRM2B
TP53

References:

Mirzayans R, et al. New Insights into p53 Signaling and Cancer Cell Response to DNA Damage: Implications for Cancer Therapy. Journal of Biomedicine & Biotechnology, 2012, 2012(5):170325.
Stegh A H. Targeting the p53 signaling pathway in cancer therapy - the promises, challenges and perils. Expert Opin Ther Targets, 2012, 16(1):67-83.
Joerger A C, Fersht A R. The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches. Annual Review of Biochemistry, 2016, 85(1):375.

* For research use only. Not intended for any clinical use.

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