Ser46 Phosphorylation Regulates p53-Dependent Apoptosis and Replicative Senescence

Feng, Lijin; Hollstein, Monica; Xu, Yiming

doi:10.4161/cc.5.23.3526

Cited by 101 publications

(83 citation statements)

References 43 publications

(65 reference statements)

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“…Our data fit this model and extend it by providing evidence that the potent oncogene MYCN induces DDR and leads to stabilization of both p53 and HIPK2, as indicated by ATM and NBS1 RNAi experiments. Interestingly, both HIPK2 and p53 S46 phosphorylation have also been involved in cellular senescence (47,48) and mouse embryo fibroblasts bearing a human mutant knock-in p53 nonphosphorylatable at p53 S46 escape from oncogene-induced senescence (49). Together with our present data, these observations support the speculation that oncogenes might induce apoptosis and/ or cell senescence due to the contemporary accumulation of both p53 and its proapoptotic/senescence activator HIPK2, via DDR.…”

Section: Discussionsupporting

confidence: 80%

MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

Petroni

Veschi

Prodosmo

et al. 2011

Molecular Cancer Research

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MYCN amplification occurs in approximately 20% of human neuroblastomas and is associated with early tumor progression and poor outcome, despite intensive multimodal treatment. However, MYCN overexpression also sensitizes neuroblastoma cells to apoptosis. Thus, uncovering the molecular mechanisms linking MYCN to apoptosis might contribute to designing more efficient therapies for MYCN-amplified tumors. Here we show that MYCN-dependent sensitization to apoptosis requires activation of p53 and its phosphorylation at serine 46. The p53 S46 kinase HIPK2 accumulates on MYCN expression, and its depletion by RNA interference impairs p53 S46 phosphorylation and apoptosis. Remarkably, MYCN induces a DNA damage response that accounts for the inhibition of HIPK2 degradation through an ATM-and NBS1-dependent pathway. Prompted by the rare occurrence of p53 mutations and by the broad expression of HIPK2 in our human neuroblastoma series, we evaluated the effects of the p53-reactivating compound Nutlin-3 on this pathway. At variance from other tumor histotypes, in MYCN-amplified neuroblastoma, Nutlin-3 further induced HIPK2 accumulation, p53 S46 phosphorylation, and apoptosis, and in combination with clastogenic agents purged virtually the entire cell population. Altogether, our data uncover a novel mechanism linking MYCN to apoptosis that can be triggered by the p53-reactivating compound Nutlin-3, supporting its use in the most difficult-to-treat subset of neuroblastoma.

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Section: Discussionsupporting

confidence: 80%

MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

Petroni

Veschi

Prodosmo

et al. 2011

Molecular Cancer Research

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“…These mice have been instrumental in understanding the functional significance of phosphorylation of c-Jun in a number of pathophysiological settings [231][232][233]. Other examples of this strategy are available [234][235][236][237]. Similar strategies to evaluate the in vivo importance of specific cysteine oxidation targets are largely lacking, and only a few knock-in mice with mutated cysteine knock-ins have been reported.…”

Section: Assessment Of the Functional Importance Of Cysteine Oxidatiomentioning

confidence: 99%

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

Janssen–Heininger¹,

Mossman²,

Heintz³

et al. 2008

Free Radical Biology and Medicine

688

652

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“…38 Phosphorylation occurs at multiple sites; although experimental evidence indicate phosphorylations at serine 15 and 20 by the ataxia telangiectasia mutated (ATM) and chk2 kinases to have a critical role in response to DNA damage, phosphorylation at serine 46, which is caused by other kinases, seems of major importance in the execution of apoptosis. [43][44][45] The mechanisms deciding between growth arrest versus apoptosis is incompletely understood, but there seems to be structural differences in the promoters of genes responding rapidly (like the CDKN1A coding for p21) as compared with the more slowly acting genes involved in apoptosis, 46,47 and integrated models for a time sequence involving protein phosphorylations and promoter activation has been proposed. 48 Drug doses may have influenced outcome as well; thus, multiple kinase inhibition by low doses of reversine were shown to induce apoptosis in a p53-dependent manner.…”

Section: Tp53mentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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Ser46 Phosphorylation Regulates p53-Dependent Apoptosis and Replicative Senescence

Cited by 101 publications

References 43 publications

MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

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