p53 in survival, death and metabolic health: a lifeguard with a licence to kill

Kruiswijk, Flore; Labuschagne, Christiaan F.; Vousden, Karen H.

doi:10.1038/nrm4007

Cited by 933 publications

(855 citation statements)

References 177 publications

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“…One factor could have been that whole pancreas was used in the analysis, which could have prevented the observation of changes in individual cell types. Kras G12D 's inhibitory effect on p53 protein levels is consistent with the effect of p53 on increasing apoptosis but inhibiting cell proliferation (11). TNFα has been found to increase pancreatic cell proliferation (20,21); therefore, it is not clear how Kras inhibition of TNFα contributes to the increase in cell proliferation observed in the mutant Kras mice.…”

Section: Discussionsupporting

confidence: 48%

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Effect of cigarette smoke exposure and mutant Kras overexpression on pancreatic cell proliferation

et al. 2017

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Abstract. Pancreatic cancer is the fourth leading cause of cancer-associated mortality. The major risk factor for pancreatic cancer is cigarette smoking. Kras mutations are commonly observed in human pancreatic cancers. The present study examined the hypothesis that exposure to cigarette smoke and overexpression of a mutant Kras gene in the pancreas affects pancreatic cell proliferation in mice. Mice overexpressing the mutant Kras gene (KRas G12D ) in the pancreas as well as wild-type mice were exposed to environmental tobacco smoke for 2 weeks. Overexpression of mutant Kras increased cell proliferation in pancreatic ductal, acinar and islet cells. Notably, cigarette smoke exposure decreased cell proliferation in pancreatic ductal and acinar cells, and had no effect in islet cells. Cigarette smoke did not affect pancreatic protein levels of tumor necrosis factor (TNF)α, p53, or cyclin D 1 , but mutant Kras overexpression slightly decreased TNFα and p53 protein levels. Therefore, pancreatic cell proliferation in mice overexpressing mutant Kras is associated with the later development of pancreatic tumors, but effects of cigarette smoke on pancreatic cell proliferation do not provide a good model for human pancreatic carcinogenesis.

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Section: Discussionsupporting

confidence: 48%

“…TNFα is a pro-inflammatory cytokine that may have promoting or inhibitory effects in pancreatic carcinogenesis (10). p53 is a tumor suppressor gene that promotes apoptosis but also inhibits cell proliferation (11). Cyclin D 1 regulates cyclin-dependent kinases (CDKs), which increase cell proliferation (12).…”

Section: Resultsmentioning

confidence: 99%

Effect of cigarette smoke exposure and mutant Kras overexpression on pancreatic cell proliferation

et al. 2017

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“…Apoptosis can contribute to the latter effect, generating a vacant niche into which cancerous cells can expand. The key tumour suppressor protein, p53 prevents cancer through multiple mechanisms 45 . In a transplantable mouse model of lymphoma, deletion of p53 from hematopoietic progenitors per se does not confer a competitive advantage over wild-type cells unless the system is stressed (in this case by irradiation) 46,47 .…”

Section: Apoptosis Cell Competition and Cancermentioning

confidence: 99%

A fate worse than death: apoptosis as an oncogenic process

2016

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“…The tumor suppressor protein p53 has numerous functions in response to DNA damage, including in the regulation of apoptosis (77). Although ATR contributes to p53 phosphorylation following exposure to UV and UV mimetics (Figs.…”

Section: Atr Promotes Cell Death In a P53-independent Manner-mentioning

confidence: 99%

ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress

Kemp

Sancar

2016

Journal of Biological Chemistry

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ATR (ataxia telangiectasia and Rad-3-related) is a protein kinase that maintains genome stability and halts cell cycle phase transitions in response to DNA lesions that block DNA polymerase movement. These DNA replication-associated features of ATR function have led to the emergence of ATR kinase inhibitors as potential adjuvants for DNA-damaging cancer chemotherapeutics. However, whether ATR affects the genotoxic stress response in non-replicating, non-cycling cells is currently unknown. We therefore used chemical inhibition of ATR kinase activity to examine the role of ATR in quiescent human cells. Although ATR inhibition had no obvious effects on the viability of non-cycling cells, inhibition of ATR partially protected nonreplicating cells from the lethal effects of UV and UV mimetics. Analyses of various DNA damage response signaling pathways demonstrated that ATR inhibition reduced the activation of apoptotic signaling by these agents in non-cycling cells. The pro-apoptosis/cell death function of ATR is likely due to transcription stress because the lethal effects of compounds that block RNA polymerase movement were reduced in the presence of an ATR inhibitor. These results therefore suggest that whereas DNA polymerase stalling at DNA lesions activates ATR to protect cell viability and prevent apoptosis, the stalling of RNA polymerases instead activates ATR to induce an apoptotic form of cell death in non-cycling cells. These results have important implications regarding the use of ATR inhibitors in cancer chemotherapy regimens.Ultraviolet (UV) photoproducts and other bulky DNA lesions block the progression of DNA and RNA polymerases and lead to the activation of various DNA damage responses that are regulated by the action of the ataxia telangiectasia and Rad-3-related (ATR) 3 protein kinase. For example, in response to DNA polymerase stalling and uncoupling from DNA helicase activity (1), ATR is thought to be recruited to singlestranded regions of DNA where it promotes a number of DNA metabolic processes that maintain genomic integrity (2-6), including replication fork stabilization, DNA synthesis and lesion bypass, homologous recombination, replication origin firing, and cell cycle delay. The importance of ATR kinase activity in these responses in replicating cells is evidenced by the fate of cells in which the catalytic activity of ATR has been genetically or pharmacologically inhibited following replication stress, which include apoptosis and entry into catastrophic mitoses (7-10). Thus, ATR helps replicating cells cope with DNA damage and replication stress by facilitating cellular processes that maintain genomic stability and avoid cell death. Given these features of ATR, there has been great interest in the development and use of selective small-molecule inhibitors of ATR kinase activity in cancer chemotherapy regimens in conjunction with compounds that damage DNA and generate replication stress (11-13). For example, several studies have shown that ATR inhibition sensitizes cancer cells to cell kill...

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p53 in survival, death and metabolic health: a lifeguard with a licence to kill

Cited by 933 publications

References 177 publications

Effect of cigarette smoke exposure and mutant Kras overexpression on pancreatic cell proliferation

Effect of cigarette smoke exposure and mutant Kras overexpression on pancreatic cell proliferation

A fate worse than death: apoptosis as an oncogenic process

ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress

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