The Double Role of P53 in Cancer and Autoimmunity and Its Potential As Therapeutic Target

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2016 Nov 30

PMID 27897991

Citations 13

Authors

Alessandra Fierabracci

Marsha Pellegrino

Affiliations

Soon will be listed here.

Abstract

p53 is a sequence-specific short-lived transcription factor expressed at low concentrations in various tissues while it is upregulated in damaged, tumoral or inflamed tissue. In normally proliferating cells, p53 protein levels and function are tightly controlled by main regulators, i.e., MDM2 (mouse double minute 2) and MDM4 proteins. p53 plays an important role due to its ability to mediate tumor suppression. In addition to its importance as a tumor suppressor, p53 coordinates diverse cellular responses to stress and damage and plays an emerging role in various physiological processes, including fertility, cell metabolism, mitochondrial respiration, autophagy, cell adhesion, stem cell maintenance and development. Interestingly, it has been recently implicated in the suppression of autoimmune and inflammatory diseases in both mice and humans. In this review based on current knowledge on the functional properties of p53 and its regulatory pathways, we discuss the potential utility of p53 reactivation from a therapeutic perspective in oncology and chronic inflammatory disorders leading to autoimmunity.

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References

Katchman B, Barderas R, Alam R, Chowell D, Field M, Esserman L . Proteomic mapping of p53 immunogenicity in pancreatic, ovarian, and breast cancers. Proteomics Clin Appl. 2016; 10(7):720-31. PMC: 5553208. DOI: 10.1002/prca.201500096. View

Egiziano G, Bernatsky S, Shah A . Cancer and autoimmunity: Harnessing longitudinal cohorts to probe the link. Best Pract Res Clin Rheumatol. 2016; 30(1):53-62. PMC: 4947510. DOI: 10.1016/j.berh.2016.03.001. View

Polyak K, Xia Y, Zweier J, Kinzler K, Vogelstein B . A model for p53-induced apoptosis. Nature. 1997; 389(6648):300-5. DOI: 10.1038/38525. View

Cools N, Van Tendeloo V, Smits E, Lenjou M, Nijs G, Van Bockstaele D . Immunosuppression induced by immature dendritic cells is mediated by TGF-beta/IL-10 double-positive CD4+ regulatory T cells. J Cell Mol Med. 2008; 12(2):690-700. PMC: 3822554. DOI: 10.1111/j.1582-4934.2007.00084.x. View

Han Z, Boyle D, Shi Y, Green D, Firestein G . Dominant-negative p53 mutations in rheumatoid arthritis. Arthritis Rheum. 1999; 42(6):1088-92. DOI: 10.1002/1529-0131(199906)42:6<1088::AID-ANR4>3.0.CO;2-E. View

Firestein G, Echeverri F, Yeo M, Zvaifler N, Green D . Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proc Natl Acad Sci U S A. 1997; 94(20):10895-900. PMC: 23522. DOI: 10.1073/pnas.94.20.10895. View

Migliorini D, Danovi D, Colombo E, Carbone R, Pelicci P, Marine J . Hdmx recruitment into the nucleus by Hdm2 is essential for its ability to regulate p53 stability and transactivation. J Biol Chem. 2001; 277(9):7318-23. DOI: 10.1074/jbc.M108795200. View

Gudkov A, Gurova K, Komarova E . Inflammation and p53: A Tale of Two Stresses. Genes Cancer. 2011; 2(4):503-16. PMC: 3135644. DOI: 10.1177/1947601911409747. View

Thomasova D, Mulay S, Bruns H, Anders H . p53-independent roles of MDM2 in NF-κB signaling: implications for cancer therapy, wound healing, and autoimmune diseases. Neoplasia. 2013; 14(12):1097-101. PMC: 3540936. DOI: 10.1593/neo.121534. View

10.

Jung D, Jin D, Hong S, Kim J, Shin J, Kim D . Foxp3 expression in p53-dependent DNA damage responses. J Biol Chem. 2010; 285(11):7995-8002. PMC: 2832950. DOI: 10.1074/jbc.M109.047985. View

11.

Ribeiro C, Rodrigues C, Moreira R, Santos M . Chemical Variations on the p53 Reactivation Theme. Pharmaceuticals (Basel). 2016; 9(2). PMC: 4932543. DOI: 10.3390/ph9020025. View

12.

Takatori H, Kawashima H, Suzuki K, Nakajima H . Role of p53 in systemic autoimmune diseases. Crit Rev Immunol. 2015; 34(6):509-16. DOI: 10.1615/critrevimmunol.2014012193. View

13.

El-Deiry W, Harper J, OConnor P, Velculescu V, Canman C, Jackman J . WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994; 54(5):1169-74. View

14.

Green D, Kroemer G . Cytoplasmic functions of the tumour suppressor p53. Nature. 2009; 458(7242):1127-30. PMC: 2814168. DOI: 10.1038/nature07986. View

15.

Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef L, Masucci M . Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med. 2004; 10(12):1321-8. DOI: 10.1038/nm1146. View

16.

Sigal A, Rotter V . Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res. 2001; 60(24):6788-93. View

17.

Ryan K, Ernst M, Rice N, Vousden K . Role of NF-kappaB in p53-mediated programmed cell death. Nature. 2000; 404(6780):892-7. DOI: 10.1038/35009130. View

18.

Barak Y, Juven T, Haffner R, Oren M . mdm2 expression is induced by wild type p53 activity. EMBO J. 1993; 12(2):461-8. PMC: 413229. DOI: 10.1002/j.1460-2075.1993.tb05678.x. View

19.

Hara T, Ogawa F, Muroi E, Komura K, Takenaka M, Hasegawa M . Anti-p53 autoantibody in systemic sclerosis: association with limited cutaneous systemic sclerosis. J Rheumatol. 2008; 35(3):451-7. View

20.

Green D, Droin N, Pinkoski M . Activation-induced cell death in T cells. Immunol Rev. 2003; 193:70-81. DOI: 10.1034/j.1600-065x.2003.00051.x. View