Putting p53 in Context

Kastenhuber, Edward R.; Lowe, Scott W.

doi:10.1016/j.cell.2017.08.028

Cited by 1,420 publications

(1,292 citation statements)

References 190 publications

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“…Although p53 loss was more potent than Abca1 loss at promoting tumorigenesis, this is not surprising because p53 frequently exerts its tumor-suppressive program through multiple effector pathways (Kastenhuber and Lowe, 2017). All tested sg Abca1 constructs produced liver tumors (Figure 7C) in which loss of Abca1 was confirmed by genomic sequencing and immunofluorescence staining for Abca1 (Figures S7A and S7B).…”

Section: Resultsmentioning

confidence: 99%

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p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression

Moon

Huang

Houlihan

et al. 2019

Cell

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282

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SUMMARY There are still gaps in our understanding of the complex processes by which p53 suppresses tumorigenesis. Here we describe a novel role for p53 in suppressing the mevalonate pathway, which is responsible for biosynthesis of cholesterol and nonsterol isoprenoids. p53 blocks activation of SREBP-2, the master transcriptional regulator of this pathway, by transcriptionally inducing the ABCA1 cholesterol transporter gene. A mouse model of liver cancer reveals that downregulation of mevalonate pathway gene expression by p53 occurs in premalignant hepatocytes, when p53 is needed to actively suppress tumorigenesis. Furthermore, pharmacological or RNAi inhibition of the mevalonate pathway restricts the development of murine hepatocellular carcinomas driven by p53 loss. Like p53 loss, ablation of ABCA1 promotes murine liver tumorigenesis and is associated with increased SREBP-2 maturation. Our findings demonstrate that repression of the mevalonate pathway is a crucial component of p53-mediated liver tumor suppression and outline the mechanism by which this occurs.

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Section: Resultsmentioning

confidence: 99%

“…p53 controls many biochemical and biological processes that limit tumor growth, the relative contribution of which can depend on genetic and tissue context (Kastenhuber and Lowe, 2017). Here we show that one of these processes can be metabolic control of the mevalonate pathway.…”

Section: Discussionmentioning

confidence: 99%

p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression

Moon

Huang

Houlihan

et al. 2019

Cell

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282

230

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“…On a variety of cellular cues, p53 escapes the control by MDM2, accumulates in the nuclei, and activates multiple genes to regulate diverse cellular processes including progression through the cell cycle, DNA damage repair, apoptosis, metabolic alterations, epigenomic modifications, shortening of telomeres, ferroptosis, etc (Haupt & Haupt, 2017). While numerous data indicate that p53 can regulate a wide array of biological processes, it should be noted that cell type, context, and specific stimuli define not just the different levels of gene expression but rather affect the transcription of very different sets of genes (Kastenhuber & Lowe, 2017). Thus, it is not surprising that depending on the cell type, p53 can generate opposite responses to the same stressor.…”

Section: P53 Is a Transcription Factormentioning

confidence: 99%

“…In addition, the kinetics of the p53 activation and the architecture of core promoters play a role in defining cellular response in a specific case: short p53 activation with rapid assembly of preinitiation complex and few rounds of RNA polymerase II reinitiation taking place at the p21 core promoter, and sustained activation with slow assembly of preinitiation complex that supports multiple rounds of transcription in case of Fas/APO1 and PUMA (Gomes & Espinosa, 2010; Morachis, Murawsky, & Emerson, 2010). The presence of epigenetic marks and other transcription factors at the target promoters may further attenuate the gene response to p53 activation (Itahana et al, 2016; Kastenhuber & Lowe, 2017). Thus, p53 functions in a complex network of regulators that support flexibility of cellular response to changing environment, depending on the cell type and state.…”

Section: P53 Is a Transcription Factormentioning

confidence: 99%

Ceramide Signaling and p53 Pathways

Jeffries¹,

Krupenko

2018

Advances in Cancer Research

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Ceramides, important players in signal transduction, interact with multiple cellular pathways, including p53 pathways. However, the relationship between ceramide and p53 is very complex, and mechanisms underlying their coregulation are diverse and not fully characterized. The role of p53, an important cellular regulator and a transcription factor, is linked to its tumor suppressor function. Ceramides are involved in the regulation of fundamental processes in cancer cells including cell death, proliferation, autophagy, and drug resistance. This regulation, however, can be pro-death or pro-survival depending on cancer type, the balance between ceramide species, the rate of their synthesis and utilization, and the availability of a specific array of downstream targets. This chapter highlights the central role of ceramide in sphingolipid metabolism, its role in cancer, specific effectors in ceramide pathways controlled by p53, and coregulation of ceramide and p53 signaling. We discuss the recent studies, which underscore the function of p53 in the regulation of ceramide pathways and the reciprocal regulation of p53 by ceramide. This complex relationship is based on several molecular mechanisms including the p53-dependent transcriptional regulation of enzymes in sphingolipid pathways, the activation of mutant p53 through ceramide-mediated alternative splicing, as well as modulation of the p53 function through direct and indirect effects on p53 coregulators and downstream targets. Further insight into the connections between ceramide and p53 will allow simultaneous targeting of the two pathways with a potential to yield more efficient anticancer therapeutics.

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“…p53 accumulation in the nucleus results in cell cycle arrest, senescence, and apoptosis. Thus, recent cancer treatment strategies attempted to induce wild type p53 nuclear retention or accumulation of p53 protein as a result of enhanced stabilization, resulting in apoptosis [55,56].…”

Section: Inactivation Of Tp53 By Mislocalizationmentioning

confidence: 99%

Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview

Wei¹,

Wu²,

Rajasekaran³

et al. 2018

Cell Physiol Biochem

226

120

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Cancer is a disease caused by the accumulation of genetic and epigenetic changes in two types of genes: tumor suppressor genes (TSGs) and proto-oncogenes. Extensive research has been conducted over the last few decades to elucidate the role of TSGs in cancer development. In cancer, loss of TSG function occurs via the deletion or inactivation of two alleles, according to Knudson’s two-hit model hypothesis. It has become clear that mutations in TSGs are recessive at the level of an individual cell; therefore, a single mutation in a TSG is not sufficient to cause carcinogenesis. However, many studies have identified candidate TSGs that do not conform with this standard definition, including genes inactivated by epigenetic silencing rather than by deletion. In addition, proteasomal degradation by ubiquitination, abnormal cellular localization, and transcriptional regulation are also involved in the inactivation of TSGs. This review incorporates these novel additional mechanisms of TSG inactivation into the existing two-hit model and proposes a revised multiple-hit model that will enable the identification of novel TSGs that can be used as prognostic and predictive biomarkers of cancer.

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Putting p53 in Context

Cited by 1,420 publications

References 190 publications

p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression

p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression

Ceramide Signaling and p53 Pathways

Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview

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