Strategies for therapeutic targeting of the p53 pathway in cancer

Wiman, Klas G.

doi:10.1038/sj.cdd.4401921

Cited by 121 publications

(94 citation statements)

References 51 publications

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“…Such approaches can include downregulating mutant p53 via siRNA technology, overexpressing the proapoptotic p63/p73 proteins or disrupting the direct protein-protein interaction between mutant p53 and p63/p73 using peptidomimetics or small molecules (Figure 1). Of note, those small molecular compounds that can reactivate mutant p53 by restoring it to wild-type conformation can also potentially release p63/p73 (reviewed by Wiman, 2006). Such compounds are potentially exciting as they may achieve the dual purpose of bringing back the activity of both p53 and its family members.…”

Section: Discussionmentioning

confidence: 99%

Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?

2007

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Although still controversial, the presence of mutant p53 in cancer cells may result in more aggressive tumors and correspondingly worse outcomes. The means by which mutant p53 exerts such pro-oncogenic activity are currently under extensive investigation and different models have been proposed. We focus here on a proposed mechanism by which a subset of tumor-derived p53 mutants physically interact with p53 family members, p63 and p73, and negatively regulate their proapoptotic function. Both cell-based assays and knock-in mice expressing mutant forms of p53 support this model. As more than half of human tumors harbor mutant forms of p53 protein, approaches aimed at disrupting the pathological interactions among p53 family members might be of clinical value.

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Section: Discussionmentioning

confidence: 99%

Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?

2007

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“…Several approaches that exploit p53 inactivation in tumors for therapy are currently being pursued, such as selective expression of killer genes in cells with nonfunctional p53 or replication-deficient viruses that can propagate only in p53-deficient cells (reviewed in Lane and Lain, 2002;McCormick, 2001). Wild-type p53 reconstitution by gene therapy has been shown to inhibit tumor growth in clinical trials (reviewed by Wiman, 2006). However, the absence of efficient delivery systems has precluded systemic administration so far.…”

Section: Introductionmentioning

confidence: 99%

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

2007

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“…Restoration of normal p53 functions in cancer cells is a promising area of research and is covered in a separate chapter on p53-targeted therapy. 1 In this chapter, we review other developments in p53 research as they relate to human disease. These include germline p53 mutations and the LiFraumeni syndrome (LFS), somatic p53 mutations in cancer and their prognostic and predictive significance, as well as recent evidence suggesting a role for p53 in non-neoplastic diseases.…”

Section: Introductionmentioning

confidence: 99%

p53 and disease: when the guardian angel fails

2006

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The p53 tumor suppressor gene (TP53) is mutated more often in human cancers than any other gene yet reported. Of importance, it is mutated frequently in the common human malignancies of the breast and colorectum and also, but less frequently, in other significant human cancers such as glioblastomas. There is also one inherited cancer predisposing syndrome called Li-Fraumeni that is caused by TP53 mutations. In this review, we discuss the significance of p53 mutations in some of the above tumors with a view to outlining how p53 contributes to malignant progression. We also discuss the usefulness of TP53 status as a prognostic marker and its role as a predictor of response to therapy. Finally, we outline some evidence that abnormalities in p53 function contribute to the etiology of other non-neoplastic diseases.

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Strategies for therapeutic targeting of the p53 pathway in cancer

Cited by 121 publications

References 51 publications

Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?

Are interactions with p63 and p73 involved in mutant p53 gain of oncogenic function?

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

p53 and disease: when the guardian angel fails

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