Regulation of p53 Function

Woods, Douglas; Vousden, Karen H.

doi:10.1006/excr.2000.5141

Cited by 304 publications

(241 citation statements)

References 126 publications

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“…Posttranslational modifications, including phosphorylation, were reportedly crucial in the stabilization and activation of p53 (Woods and Vousden, 2001;Brooks and Gu, 2003). Given that NUAK1 interacted with p53, we investigated whether the kinase NUAK1 phosphorylated p53 while interacting with it.…”

Section: Nuak1 Directly Phosphorylates P53mentioning

confidence: 99%

A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation

Hou

Liu

et al. 2011

Oncogene

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It has been suggested that adenosine monophosphateactivated protein kinase (AMPK) and 12 AMPK-related kinases (ARK), including novel (nua) kinase family 1 (NUAK1), are activated by master kinase LKB1, a major tumor suppressor. Apart from evidence to suggest that NUAK1 participates in induction of tumor survival, invasion and p53-independent cellular senescence, its detailed biological functions remain unclear. Here we showed that in the presence of wild-type LKB1, NUAK1 directly interacts with and phosphorylates p53 in vitro and in vivo. The phosphorylation of p53 induced by LKB1 required the kinase activity of NUAK1 and phosphorylation of NUAK1 at Thr211 by LKB1 was essential for its kinase activity, which leads to the conclusion that LKB1 activates NUAK1 and regulates phosphorylation of p53 through the NUAK1 kinase, at least partially. LKB1/ NUAK1 activation leads to cell cycle arrest at the G 1 /S border by inducing expression of p21/WAF1. Under the regulation of LKB1, NUAK1 interacts with p53 in the nucleus and binds to the p53-responsive element of p21/WAF1 promoter. These findings have highlighted a novel role for NUAK1 in LKB1-related signaling pathways; NUAK1 can regulate cell proliferation and exert tumor suppression through direct interaction with p53.

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Section: Nuak1 Directly Phosphorylates P53mentioning

confidence: 99%

A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation

Hou

Liu

et al. 2011

Oncogene

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“…10 Apoptosis can prevent cancerous cells from proliferating, but malignancy is often associated with malfunctioning pro-apoptotic machinery in cells. In fact, half of all human cancers are associated with a mutation within the p53 gene, while many others show deficiency in the p53-mediated pathway.…”

Section: Regulation Of P53 By Ptmsmentioning

confidence: 99%

“…For instance, phosphorylation of Ser392, which is induced upon genotoxic radiation, activates sequence-specific DNA binding in vitro. 10 Similarly, phosphorylation of Ser315 also enhances sequence-specific DNA binding in vitro, and mutation of this site to alanine reduces the transcriptional activity of p53 in vivo. 12 Notably, phosphorylation at Ser315 as well as Ser33 and Thr81 promotes binding of p53 to the peptidyl-prolyl isomerase Pin1.…”

Section: Regulation Of P53 By Ptmsmentioning

confidence: 99%

“…The transcription factor has been demonstrated to bear numerous other modifications, including ubiquitination, sumoylation (the addition of the small ubiquitin-like protein SUMO), O-GlcNAc glycosylation and ribosylation. 10 While these other modifications will not be considered in detail here, the addition of ubiquitin plays a particularly important role in p53 stability. 17 Interestingly, an early candidate for a p53-stabilizing drug, CP-31398, identified by Pfizer, functions in vivo by inhibiting the ubiquitination of p53.…”

Section: Regulation Of P53 By Ptmsmentioning

confidence: 99%

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A ‘molecular switchboard’—covalent modifications to proteins and their impact on transcription

Khidekel

Hsieh‐Wilson

2004

Org. Biomol. Chem.

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Proteins undergo a remarkable variety of posttranslational modifications, with more than 200 distinct modifications identified to date. Increasing evidence suggests that many proteins bear multiple, distinct modifications, and the ability of one modification to antagonize or synergize the deposition of another can have significant biological consequences. Here, we illustrate the importance of posttranslational modifications within the context of transcriptional regulation, and we offer a perspective on the emerging role of combinatorial networks of modifications. Finally, we discuss the potential for chemical approaches to transform our understanding of the field.

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“…Pathway analysis of the differently regulated proteins suggests an increase in p53 activity in the p53 K317R p53 is one of the most important mammalian tumor suppressor proteins. It has been found to be mutated in approximately half of human cancers (1), and its functioning is frequently altered in many of the remainder (2). p53 is able to induce apoptosis, cell cycle arrest, DNA repair, and senescence in part through the activation or repression of numerous genes, including the cyclin kinase inhibitor CDKN1A (p21) and the proapoptotic proteins PUMA, NOXA, and PIDD (3).…”

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confidence: 99%

Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes

Jenkins

Mazur

Rossi

et al. 2008

Molecular & Cellular Proteomics

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The tumor suppressor protein p53 is a sequence-specific transcription factor that has crucial roles in apoptosis, cell cycle arrest, cellular senescence, and DNA repair. Following exposure to a variety of stresses, p53 becomes posttranslationally modified with concomitant increases in activity and stability. To better understand the role of acetylation of Lys-317 in mouse p53, the effect of ionizing radiation (IR) on the thymocytes of p53 K317R knock-in mice was studied at the global level. Using cleavable ICAT quantitative mass spectrometry, the effect of IR on protein levels in either the wild type or p53 K317R thymocytes was determined. We found 102 proteins to be significantly affected by IR in the wild type thymocytes, including several whose expression has been shown to be directly regulated by p53. When the effects of IR in the wild type and p53 K317R samples were compared, 46 proteins were found to be differently affected (p < 0.05). The p53 K317R mutation has widespread effects on specific protein levels following IR, including the levels of proteins involved in apoptosis, transcription, and translation. Pathway analysis of the differently regulated proteins suggests an increase in p53 activity in the p53 K317R thymocytes as well as a decrease in tumor necrosis factor ␣ signaling. These results suggest that acetylation of Lys-317 modulates the functions of p53 and influences the cross-talk between

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Regulation of p53 Function

Cited by 304 publications

References 126 publications

A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation

A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation

A ‘molecular switchboard’—covalent modifications to proteins and their impact on transcription

Quantitative Proteomics Analysis of the Effects of Ionizing Radiation in Wild Type and p53K317R Knock-in Mouse Thymocytes

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