Abstract
About half of all human tumors contain an inactivating mutation of p53, while in the remaining tumors, the p53 pathway is frequently abrogated by alterations of other components of its signaling pathway. In humans, the p53 tumor suppressor is part of a small gene family that includes two other members, p73 and p63, structurally and functionally related to p53. Accumulating evidences indicate that all p53-family proteins function as molecular hubs of a highly interconnected signaling network that coordinates cell proliferation, differentiation and death in response to physiological inputs and oncogenic stress. Therefore, not only the p53-pathway but the entire “p53-family pathway” is a primary target for cancer drug development. In particular, the p53-related protein p73 has a crucial role in determining cellular responses to chemotherapy, and can vicariate p53 functions in triggering cell death after DNA damage in multiple experimental models. The biology and regulation of p73 is complex, since the TP73 gene incorporates both tumor-suppressive and protooncogenic functions. However, the p73 gene is rarely mutated in tumors, so appropriate pharmacological manipulation of the p73 pathway is a very promising approach for cancer therapy. Here we provide an overview of the principal mechanism of p73 regulation, and describe several examples of pharmacological tools that can induce p73 accumulation and function by acting on upstream p73 modulators or displacing inhibitory p73 interactors. A better understanding of how the p73 pathway works is mandatory to discover additional players intervening in this pathway and has important implications for the improvement of cancer treatment with the development of new molecules or with the reposition of currently available drugs.
Keywords: p73 tumor suppressor, TA-p73, ΔN-p73, mutant p53, apoptosis, cancer, small molecules, peptides, aptamers, cell death, anti-apoptotic, C-terminus, hydrocephalus, oncogenic, inhibits, MDM2, E2F1, chemotherapeutic, phosphorylation
Current Pharmaceutical Design
Title: p73 as a Pharmaceutical Target for Cancer Therapy
Volume: 17 Issue: 6
Author(s): Andrea Bisso, Licio Collavin and Giannino Del Sal
Affiliation:
Keywords: p73 tumor suppressor, TA-p73, ΔN-p73, mutant p53, apoptosis, cancer, small molecules, peptides, aptamers, cell death, anti-apoptotic, C-terminus, hydrocephalus, oncogenic, inhibits, MDM2, E2F1, chemotherapeutic, phosphorylation
Abstract: About half of all human tumors contain an inactivating mutation of p53, while in the remaining tumors, the p53 pathway is frequently abrogated by alterations of other components of its signaling pathway. In humans, the p53 tumor suppressor is part of a small gene family that includes two other members, p73 and p63, structurally and functionally related to p53. Accumulating evidences indicate that all p53-family proteins function as molecular hubs of a highly interconnected signaling network that coordinates cell proliferation, differentiation and death in response to physiological inputs and oncogenic stress. Therefore, not only the p53-pathway but the entire “p53-family pathway” is a primary target for cancer drug development. In particular, the p53-related protein p73 has a crucial role in determining cellular responses to chemotherapy, and can vicariate p53 functions in triggering cell death after DNA damage in multiple experimental models. The biology and regulation of p73 is complex, since the TP73 gene incorporates both tumor-suppressive and protooncogenic functions. However, the p73 gene is rarely mutated in tumors, so appropriate pharmacological manipulation of the p73 pathway is a very promising approach for cancer therapy. Here we provide an overview of the principal mechanism of p73 regulation, and describe several examples of pharmacological tools that can induce p73 accumulation and function by acting on upstream p73 modulators or displacing inhibitory p73 interactors. A better understanding of how the p73 pathway works is mandatory to discover additional players intervening in this pathway and has important implications for the improvement of cancer treatment with the development of new molecules or with the reposition of currently available drugs.
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Cite this article as:
Bisso Andrea, Collavin Licio and Del Sal Giannino, p73 as a Pharmaceutical Target for Cancer Therapy, Current Pharmaceutical Design 2011; 17 (6) . https://dx.doi.org/10.2174/138161211795222667
DOI https://dx.doi.org/10.2174/138161211795222667 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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