Reactivation of mutant p53: molecular mechanisms and therapeutic potential

Selivanova, Galina; Wiman, Klas G.

doi:10.1038/sj.onc.1210295

Cited by 175 publications

(127 citation statements)

References 98 publications

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“…For example, APC in colorectal cancer, BRCA1 in breast and ovarian cancer, p53 in colorectal, pancreatic, brain and liver cancer, SMAD4 in colorectal and pancreatic cancer. 16 Some of these genetic alterations have become useful as diagnostic markers, prognostic markers or therapeutic targets. Compiling the cancer genetic profile of HNSCC remains a top priority for understanding and treating the disease.…”

Section: Resultsmentioning

confidence: 99%

Multiple tumor-suppressor genes on chromosome 3p contribute to head and neck squamous cell carcinoma tumorigenesis

Lee

Schönleben

Banuchi

et al. 2010

Cancer Biology & Therapy

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Section: Resultsmentioning

confidence: 99%

Multiple tumor-suppressor genes on chromosome 3p contribute to head and neck squamous cell carcinoma tumorigenesis

Lee

Schönleben

Banuchi

et al. 2010

Cancer Biology & Therapy

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“…41 Thus, targeting v2 inhibition specifically to cancer cells, for example, with nanocarriers, antibody-drug conjugates, or other approaches, 42,43 may maintain v2/p53-dependent protection of normal cells while sensitizing tumor cells to DNA-damaging drugs. Furthermore, as sensitization of cancer cells to therapy by v2 depletion appears to require p53, inhibition of v2 along with administration of small molecules that activate wild-type p53 or revert mutant p53 to function like wild-type p53 (e.g., nutlin-3, RITA, PK7088 [44][45][46] ) may also be beneficial for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

et al. 2016

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Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a stress-response gene that has been associated with cancer, but no studies have differentiated among or defined the regulation or function of any of its several recently described expression variants. We found that TNFAIP8 variant 2 (v2) is overexpressed in multiple human cancers, whereas other variants are commonly downregulated in cancer (v1) or minimally expressed in cancer or normal tissue (v3-v6). Silencing v2 in cancer cells induces p53-independent inhibition of DNA synthesis, widespread binding of p53, and induction of target genes and p53-dependent cell cycle arrest and DNA damage sensitization. Cell cycle arrest induced by v2 silencing requires p53-dependent induction of p21. In response to the chemotherapeutic agent doxorubicin, p53 regulates v2 through binding to an intragenic enhancer, together indicating that p53 and v2 engage in complex reciprocal regulation. We propose that TNFAIP8 v2 promotes human cancer by broadly repressing p53 function, in essence offsetting p53-dependent tumor suppression. Cell Death and Differentiation (2017) 24, 181-191; doi:10.1038/cdd.2016 published online 11 November 2016 Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is the founding member of a recently described family of environmental stress response genes that are induced by TNFα. TNFAIP8 has been shown to promote or inhibit apoptosis, depending on cell type and context. 1,2 Although little is known about TNFAIP8, it has recently been found to be overexpressed in a wide range of human cancers. Some studies have suggested protumor functions for TNFAIP8, including enhancement of cell survival, proliferation, and metastasis [3][4][5][6][7][8][9] and resistance to cancer chemotherapeutics in mice. 4,10Nonetheless, nothing is known about how TNFAIP8 influences responses to DNA damage in cancer cells. Moreover, several transcript variants from the TNFAIP8 gene were recently registered in the NCBI reference sequence database, but no study to date has differentiated among them or defined the factors that govern their expression.The tumor suppressor p53 is a transcription factor that regulates many biological processes through its target gene network. Some of the well-characterized p53 target genes including p21/CDKN1A, growth arrest and DNA damageinducible 45a (GADD45A) and Bcl-2-like protein 4 (BAX) together promote senescence, cell cycle arrest, and apoptosis, all of which may contribute to the tumor suppressing functions of p53. 11,12Additional noncanonical tumorsuppressive pathways from p53 have recently been identified. [13][14][15] Improved characterization of the p53 DNAbinding sequence with modern sequencing techniques has led to the identification of a rapidly expanding list of p53 target genes. [16][17][18] Continued identification of these genes and characterization of their mechanisms of regulation and function will be critical to a full understanding of p53 and for full realization of opportunities to intervene upon p53 in cancer.Here, we identify ...

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“…Activation or suppression of those promoters has the most prominent role in p53-dependent apoptosis, cell-cycle arrest and other elements of the p53 antitumor response (Laptenko and Prives, 2006). Therefore, p53-related anticancer therapies require methods that would restore WT structure and function of inactivated p53 (Selivanova and Wiman, 2007). However, it is also apparent that in normal cells there must be a set of mechanisms that maintains WT p53 in the state allowing for activation of its target genes.…”

Section: Introductionmentioning

confidence: 99%

Hsp70 molecular chaperones are required to support p53 tumor suppressor activity under stress conditions

et al. 2009

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p53 as an unstable protein in vitro likely requires stabilizing factors to act as a tumor suppressor in vivo. Here, we show that in human cells transfected with wildtype (WT) p53, Hsp90 and Hsp70 molecular chaperones maintain the p53 native conformation under heat-shock conditions (42 1C) as well as assist p53 refolding at 37 1C, during the recovery from heat shock. We also show that the interaction of WT p53 with WAF1 promoter in cells is sensitive to Hsp70 and Hsp90 inhibition already at 37 1C and further decreased on heat shock. The influence of chaperones on p53 binding to the WAF1 promoter sequence has been confirmed in vitro, using highly purified proteins. Hsp90 stabilizes the binding of p53 to the promoter sequence at 37 1C, whereas under heat-shock conditions the requirement for the Hsp70-Hsp40 system and its cooperation with Hsp90 increases. Hop co-chaperone additionally stimulates these reactions. Interestingly, the combined Hsp90 and Hsp70-Hsp40 allow for a limited in vitro restoration of the DNA-binding activity by the p53 oncogenic variant R249S and affect its conformation in cells. Our results indicate for the first time that, especially under stress conditions, not only Hsp90 but also Hsp70 is required for the chaperoning of WT and R249S p53.

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Reactivation of mutant p53: molecular mechanisms and therapeutic potential

Cited by 175 publications

References 98 publications

Multiple tumor-suppressor genes on chromosome 3p contribute to head and neck squamous cell carcinoma tumorigenesis

Multiple tumor-suppressor genes on chromosome 3p contribute to head and neck squamous cell carcinoma tumorigenesis

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

Hsp70 molecular chaperones are required to support p53 tumor suppressor activity under stress conditions

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