Pathologies Associated with the p53 Response

Gudkov, Andrei V.; Komarova, Elena A.

doi:10.1101/cshperspect.a001180

Cited by 98 publications

(103 citation statements)

References 197 publications

(239 reference statements)

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“…p53, however, induces genes that encode cell cycle checkpoint regulators (e.g., 21), pro-apoptotic factors (e.g., BAX, PUMA, NOXA), and secreted growth inhibitors. 27 Consistent with these functional differences, p53 and NF-κB are deregulated in opposite directions in tumors. Although p53 is a tumor suppressor that is commonly inactivated, NF-κB behaves like an oncogene, showing constitutive activation in the majority of cancers.…”

Section: P53 and Nf-κb: Opposite Approaches To Physiological Stress Rsupporting

confidence: 60%

“…84 Acute activation of p53 following systemic genotoxic stress associated with exposure to ionizing radiation or treatment with cytotoxic chemotherapeutic drugs results in massive apoptosis in sensitive tissues, such as the hematopoietic system, gastrointestinal tract, and hair follicles. 27 These p53-dependent responses contribute to development of acute radiation syndrome and the side effects of chemotherapy that cause morbidity and treatment-limiting toxicities in millions of cancer patients. 27,85 Thus, for both NF-κB and p53, normal physiological responses can lead to lethal consequences if activated to excessive levels.…”

Section: Use Of P53-nf-κb Mutual Antagonism To Treat Pathologies Assomentioning

confidence: 99%

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Inflammation and p53: A Tale of Two Stresses

Gudkov

Gurova²,

Komarova³

2011

Genes & Cancer

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177

145

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Numerous observations indicate a strong link between chronic inflammation and cancer. This link is supported by substantial experimental evidence indicating mutual negative regulation of NF-κB, the major regulator of inflammation, and p53, the major tumor suppressor. This antagonistic relationship reflects the opposite principles of the physiological responses driven by these transcription factors, which act as sensors and mediators of intrinsic and extrinsic cell stresses, respectively. Constitutive activation of NF-κB, the underlying cause of chronic inflammation, is a common acquired characteristic of tumors. A variety of experimental methods have been used to demonstrate that constitutive activation of NF-κB reduces the tumor suppressor activity of p53, thereby creating permissive conditions for dominant oncogene-mediated transformation. Loss of p53 activity is also a characteristic of the majority of tumors and results in unleashed inflammatory responses due to loss of p53-mediated NF-κB suppression. On the other hand, in natural or pharmacological situations of enforced p53 activation, NF-κB activity, inflammation, and immune responses are reduced, resulting in different pathologies. It is likely that the chronic inflammation that is commonly acquired in various tissues of older mammals leads to general suppression of p53 function, which would explain the increased risk of cancer observed in aging animals and humans. Although the molecular mechanisms underlying reciprocal negative regulation of p53 and NF-κB remain to be deciphered, this phenomenon has important implications for pharmacological prevention of cancer and aging and for new approaches to control inflammation.

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Section: P53 and Nf-κb: Opposite Approaches To Physiological Stress Rsupporting

confidence: 60%

Section: Use Of P53-nf-κb Mutual Antagonism To Treat Pathologies Assomentioning

confidence: 99%

Inflammation and p53: A Tale of Two Stresses

Gudkov

Gurova²,

Komarova³

2011

Genes & Cancer

Self Cite

177

145

View full text Add to dashboard Cite

show abstract

“…Hence, absence of p53 may lead to defective cell-cycle arrest and hence, allow the cells to undergo apoptosis. Several reports have supported this paradigm (Janicke et al, 2008;Gudkov and Komarova, 2010). For example, absence of p53 has been shown to promote taxol-mediated death owing to failure of cell arrest in the G 1 phase of the cell cycle, and hence, allowing cells to accumulate in the G 2 /M phase where they undergo mitotic cell death (Vikhanskaya et al, 1998).…”

Section: Introductionmentioning

confidence: 96%

p53 promotes cellular survival in a context-dependent manner by directly inducing the expression of haeme-oxygenase-1

Nam

Sabapathy

2011

Oncogene

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“…When p53-positive mice were treated with doxorubicin, upregulation of p53 was exhibited in the rapidly dividing cells of the bone marrow, spleen, thymus, and small intestine, associating with massive apoptosis in these tissues. In p53-null mice, this toxicity was largely avoided (11), hinting that p53 inhibition may offer cancer patients some degree of protection from the toxicity of p53-activating chemotherapeutics (12).…”

Section: Introductionmentioning

confidence: 99%

Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity

et al. 2017

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Chemotoxicity due to unwanted p53 activation in the bone marrow remains an unmet clinical challenge. Doxorubicin, a firstline chemotherapy drug, often causes myelosuppression in patients, thus limiting its effectiveness. In this study, we discovered that C646, a reversible p300 inhibitor, downregulates p53 transcription and selectively protects noncancerous cells from p53-dependent apoptosis. C646 treatment blocked acetylation of specific lysine residues that regulate p53 activity. Exploitation of differential p53 genetic backgrounds between human hematopoietic and colorectal cancer cells improved the therapeutic index of doxorubicin with C646 cotreatment. C646 administration in mice afflicted with p53-mutant tumors protected them from doxorubicin-induced neutropenia and anemia while retaining antitumor efficacy. We deduce that temporary and reversible inhibition of p53 acetylation in cancer subjects, especially those with p53-mutant tumors, may protect them from severe chemotoxicity while allowing treatment regimens to effectively proceed.Cancer Res; 77(16); 4342-54. Ó2017 AACR.

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Pathologies Associated with the p53 Response

Cited by 98 publications

References 197 publications

Inflammation and p53: A Tale of Two Stresses

Inflammation and p53: A Tale of Two Stresses

p53 promotes cellular survival in a context-dependent manner by directly inducing the expression of haeme-oxygenase-1

Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity

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