Lysines in the tetramerization domain of p53 selectively modulate G1 arrest

Beckerman, Rachel; Yoh, Kathryn E.; Mattia-Sansobrino, Melissa; Zupnick, Andrew; Laptenko, Oleg; Karni-Schmidt, Orit; Ahn, Jin-Woo; Byeon, In‐Ja L.; Keezer, Susan M.; Prives, Carol

doi:10.1080/15384101.2016.1170270

Cited by 15 publications

(10 citation statements)

References 85 publications

(102 reference statements)

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“…Loss of function can also occur by mutating lysines 351 and 357 within the OD of p53 to glutamine residues; a p53 variant that forms tetramers when expressed in H1299 p53-null cells and impairs their cell cycle arrest function while retaining their ability to undergo cell death. 36 In contrast, the charge reversal mutation K351E in conjunction with E343K and E346K within the OD dimer-dimer interface of p53-CR forms tetramers in H1299 cells that retain all wt p53 functions.…”

Section: Discussionmentioning

confidence: 99%

p53 oligomerization status modulates cell fate decisions between growth, arrest and apoptosis

et al. 2016

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Mutations in the oligomerization domain of p53 are genetically linked to cancer susceptibility in Li-Fraumeni Syndrome. These mutations typically alter the oligomeric state of p53 and impair its transcriptional activity. Activation of p53 through tetramerization is required for its tumor suppressive function by inducing transcriptional programs that lead to cell fate decisions such as cell cycle arrest or apoptosis. How p53 chooses between these cell fate outcomes remains unclear. Here, we use 5 oligomeric variants of p53, including 2 novel p53 constructs, that yield either monomeric, dimeric or tetrameric forms of p53 and demonstrate that they induce distinct cellular activities and gene expression profiles that lead to different cell fate outcomes. We report that dimeric p53 variants are cytostatic and can arrest cell growth, but lack the ability to trigger apoptosis in p53-null cells. In contrast, p53 tetramers induce rapid apoptosis and cell growth arrest, while a monomeric variant is functionally inactive, supporting cell growth. In particular, the expression of pro-arrest CDKN1A and pro-apoptotic P53AIP1 genes are important cell fate determinants that are differentially regulated by the oligomeric state of p53. This study suggests that the most abundant oligomeric species of p53 present in resting cells, namely p53 dimers, neither promote cell growth or cell death and that shifting the oligomeric state equilibrium of p53 in cells toward monomers or tetramers is a key parameter in p53-based cell fate decisions.

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Section: Discussionmentioning

confidence: 99%

p53 oligomerization status modulates cell fate decisions between growth, arrest and apoptosis

et al. 2016

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“…This then assembles with another dimer to form a tetrameric structure that is stabilized by hydrophobic interactions between oligomerisation domains. Recently, lysine residues located within the oligomerisation domain, unessential for p53 s tetramerization capability, have been identified to selectively modulate p53-mediated apoptosis and cell-cycle arrest [51,52].…”

Section: Conservation and Structure Of P53 And Its Isoformsmentioning

confidence: 99%

The Emerging Landscape of p53 Isoforms in Physiology, Cancer and Degenerative Diseases

Anbarasan

Bourdon

2019

IJMS

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p53, first described four decades ago, is now established as a master regulator of cellular stress response, the "guardian of the genome". p53 contributes to biological robustness by behaving in a cellular-context dependent manner, influenced by several factors (e.g., cell type, active signalling pathways, the type, extent and intensity of cellular damage, cell cycle stage, nutrient availability, immune function). The p53 isoforms regulate gene transcription and protein expression in response to the stimuli so that the cell response is precisely tuned to the cell signals and cell context. Twelve isoforms of p53 have been described in humans. In this review, we explore the interactions between p53 isoforms and other proteins contributing to their established cellular functions, which can be both tumour-suppressive and oncogenic in nature. Evidence of p53 isoform in human cancers is largely based on RT-qPCR expression studies, usually investigating a particular type of isoform. Beyond p53 isoform functions in cancer, it is implicated in neurodegeneration, embryological development, progeroid phenotype, inflammatory pathology, infections and tissue regeneration, which are described in this review.

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“…It should be remembered that ETS2 binds to the tetramerization domain of p53 (173–175), which is thought to be functionally intact in both WTp53 and mtp53. Then the question is how ETS2 distinguishes between mtp53 and WTp53.…”

Section: Ets1 and Ets2mentioning

confidence: 99%

Aberrant expression of ETS1 and ETS2 proteins in cancer

Fry

Inoue

2018

Cancer Rep Rev

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The ETS transcription factors regulate expression of genes involved in normal cell development, proliferation, differentiation, angiogenesis, and apoptosis, consisting of 28 family members in humans. Dysregulation of these transcription factors facilitates cell proliferation in cancers, and several members participate in invasion and metastasis by activating gene transcription. ETS1 and ETS2 are the founding members of the ETS family and regulate transcription by binding to ETS sequences. They are both involved in oncogenesis and tumor suppression depending on the biological situations used. The essential roles of ETS proteins in human telomere maintenance have been suggested, which have been linked to creation of new Ets binding sites. Recently, preferential binding of ETS2 to gain-of-function mutant p53 and ETS1 to wild type p53 (WTp53) has been suggested, raising the tumor promoting role for the former and tumor suppressive role for the latter. The oncogenic and tumor suppressive functions of ETS1 and 2 proteins have been discussed.

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Lysines in the tetramerization domain of p53 selectively modulate G1 arrest

Cited by 15 publications

References 85 publications

p53 oligomerization status modulates cell fate decisions between growth, arrest and apoptosis

p53 oligomerization status modulates cell fate decisions between growth, arrest and apoptosis

The Emerging Landscape of p53 Isoforms in Physiology, Cancer and Degenerative Diseases

Aberrant expression of ETS1 and ETS2 proteins in cancer

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