Recent advances in p53 research: an interdisciplinary perspective

Abstract

The TP53 gene is one of the most studied genes in human cancer. In recent years, considerable interest was focused on mutant p53, the abnormal protein product of TP53 somatic or germline alleles with missense mutations that often accumulate in cancer cells. There is now compelling experimental evidence that many mutations can exert mutant-specific, gain-of-function effects by perturbing the regulation of expression of multiple genes. This notion is supported by the observation that targeted mutant p53 expression enhances the formation of specific cancers in the mouse even in the absence of wild-type p53 expression. In addition, clinical studies are producing a wealth of functional pathway data demonstrating correlations between specific TP53 mutations and gene expression patterns identified by transcriptome studies. These correlations imply that alteration of p53 function is critical in shaping gene expression patterns in cancer. Finally, progress is being made in the development of new therapeutic approaches targeting p53 alterations. Key advances regarding the structural, biochemical and functional properties of normal and mutant p53 proteins, their abnormal regulation and distribution in human cancers, and their associations with clinical and pathological cancer characteristics are reviewed. New opportunities for translational research for improving cancer detection, prognosis, prevention and therapy based upon the integration of this knowledge are described.

Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms

“…Correction for ''Integrin ␤ 1 -focal adhesion kinase signaling directs the proliferation of metastatic cancer cells disseminated in the lungs,'' by Tsukasa Shibue and Robert A. Weinberg, which appeared in issue 25 The authors note that on page 10292, right column, first full paragraph, the following sentence should be added after the third sentence: ''These changes in mRNA expression may account for the previously reported observed increases in the nuclear staining of p16 Ink4a and p27 Kip1 in the D2.0R cells propagated under Matrigel-based, 3D culture conditions similar to those described here (15).'' On page 10292, right column, third full paragraph, the following sentence should be added after the last sentence: ''The absence of actin stress fibers in the nonmetastatic D2.0R cells and the presence of these fibers in the D2A1 cells are consistent with the behavior of these cells previously reported by Green and colleagues (15).''…”

Sarcomas in TP53 germline mutation carriers

“…In addition, some mutations can cause ''gain of function'' whereby mutant p53 protein assumes an oncogenic role and promotes tumor development. [16][17][18] To date, a total of 532 families or individuals with germline TP53 mutations have been reported in the peerreviewed literature. 19 Information on these mutations, on tumor pathologies and localization, and on age of diagnosis in mutation carriers is compiled into the TP53 database maintained at the International Agency for Research on Cancer (IARC).…”

Preferential killing of p53-deficient cancer cells by reversine

“…13,14 Finally, both pharmacological and genetic strategies aimed at reconstituting the oncosuppressive functions of p53 have been shown to exert consistent anticancer effects in vivo in a wide array of preclinical models of neoplasia as well as in cancer patients participating in clinical trials (reviewed in ref. 9).…”