Che-1 Promotes Tumor Cell Survival by Sustaining Mutant p53 Transcription and Inhibiting DNA Damage Response Activation

Bruno, Tiziana; Desantis, Agata; Bossi, Gianluca; Agostino, Silvia Di; Socolovschi, Cristina; Nicola, Francesca De; Iezzi, Simona; Franchitto, Annapaola; Benassi, Barbara; Galanti, Sergio; Rosa, Francesca La; Floridi, Aristide; Bellacosa, Alfonso; Passananti, Claudio; Blandino, Giovanni; Fanciulli, Maurizio

doi:10.1016/j.ccr.2010.05.027

Cited by 49 publications

(64 citation statements)

References 51 publications

(76 reference statements)

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“…It is noteworthy that Che-1 inhibition intensifies the cytotoxicity of DNA-damaging anticancer drugs, in such way reverting the chemoresistance of several tumor cell lines (11)(12)(13). Consistent with these findings, Che-1 depletion strongly decreases mutant p53 expression in human cancer cells, activates DNA damage checkpoint, and induces p73 transcription and apoptosis in these cells (14).…”

supporting

confidence: 71%

Centrosomal Che-1 Protein Is Involved in the Regulation of Mitosis and DNA Damage Response by Mediating Pericentrin (PCNT)-dependent Chk1 Protein Localization

Socolovschi

Bruno

Desantis

et al. 2013

Journal of Biological Chemistry

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Background: Che-1 is an RNA polymerase II-binding protein involved in gene transcription, cell proliferation, and DNA damage response. Results: Che-1 localizes at interphase centrosomes. Che-1 inhibition abolishes Chk1 localization at centrosomes, advancing entry into mitosis. Conclusion: Che-1 acts like an upstream regulator of Chk1 centrosomal functions. Significance: Che-1 inhibition might potentiate tumor cell sensitivity to antimitotic drugs.

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supporting

confidence: 71%

Centrosomal Che-1 Protein Is Involved in the Regulation of Mitosis and DNA Damage Response by Mediating Pericentrin (PCNT)-dependent Chk1 Protein Localization

Socolovschi

Bruno

Desantis

et al. 2013

Journal of Biological Chemistry

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“…As p73 shares many transcriptional targets with p53, activation of p73 following DNA damage can be inhibited by high stable levels of p53 mut through dominant negative suppression of classical p53 targets [66, 67]. Therefore we reasoned that the increased sensitivity to IR following reduction in p53 mut stability may be due to derepression of p73 function.…”

Section: Resultsmentioning

confidence: 99%

AKT regulates NPM dependent ARF localization and p53mut stability in tumors

et al. 2014

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Nucleophosmin (NPM) is known to regulate ARF subcellular localization and MDM2 activity in response to oncogenic stress, though the precise mechanism has remained elusive. Here we describe how NPM and ARF associate in the nucleoplasm to form a MDM2 inhibitory complex. We find that oligomerization of NPM drives nucleolar accumulation of ARF. Moreover, the formation of NPM and ARF oligomers antagonizes MDM2 association with the inhibitory complex, leading to activation of MDM2 E3-ligase activity and targeting of p53. We find that AKT phosphorylation of NPM-Ser48 prevents oligomerization that results in nucleoplasmic localization of ARF, constitutive MDM2 inhibition and stabilization of p53. We also show that ARF promotes p53 mutant stability in tumors and suppresses p73 mediated p21 expression and senescence. We demonstrate that AKT and PI3K inhibitors may be effective in treatment of therapeutically resistant tumors with elevated AKT and carrying gain of function mutations in p53. Our results show that the clinical candidate AKT inhibitor MK-2206 promotes ARF nucleolar localization, reduced p53mut stability and increased sensitivity to ionizing radiation in a xenograft model of pancreatic cancer. Analysis of human tumors indicates that phospho-S48-NPM may be a useful biomarker for monitoring AKT activity and in vivo efficacy of AKT inhibitor treatment. Critically, we propose that combination therapy involving PI3K-AKT inhibitors would benefit from a patient stratification rationale based on ARF and p53mut status.

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“…1C, D, E). Since AATF is widely believed to be transcriptional adaptor molecule rather than intrinsic transcriptional factor [10], it was reasonable to assume that AATF may be modulating these genes through miR-2909 RNomics which involves the repression of KLF4 expression coupled with up-regulation of SP1 gene expression [11]. Hence it became imperative to explore such a possibility.…”

Section: Aatf Rnome Regulates Genomic Expressionmentioning

confidence: 99%

Mitochondrial uncoupling protein (UCP2) gene expression is regulated by miR-2909

Kaul

Sharma

Garg

2015

Blood Cells, Molecules, and Diseases

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Che-1 Promotes Tumor Cell Survival by Sustaining Mutant p53 Transcription and Inhibiting DNA Damage Response Activation

Cited by 49 publications

References 51 publications

Centrosomal Che-1 Protein Is Involved in the Regulation of Mitosis and DNA Damage Response by Mediating Pericentrin (PCNT)-dependent Chk1 Protein Localization

Centrosomal Che-1 Protein Is Involved in the Regulation of Mitosis and DNA Damage Response by Mediating Pericentrin (PCNT)-dependent Chk1 Protein Localization

AKT regulates NPM dependent ARF localization and p53mut stability in tumors

Mitochondrial uncoupling protein (UCP2) gene expression is regulated by miR-2909

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