MDM2 and Fbw7 cooperate to induce p63 protein degradation following DNA damage and cell differentiation

Galli, Francesco; Rossi, Mariangela; D’Alessandra, Yuri; Simone, Marco De; Lopardo, Teresa; Haupt, Ygal; Alsheich-Bartok, Osnat; Anzi, Shira; Shaulian, Eitan; Calabrò, Viola; Mantia, Girolama La; Guerrini, Luisa

doi:10.1242/jcs.061010

Cited by 92 publications

(103 citation statements)

References 50 publications

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“…Because of key roles of p63 in cell growth and proliferation, apoptosis and differentiation, p63 levels are tightly regulated, mainly by the ubiquitin-dependent proteasomal degradation pathway (38). Recent studies have shown that degradation of p63 during KC differentiation by E3 ubiquitin ligase requires GSK3 kinase activity (39). Given that GSK3 is a potential substrate for PKD signaling (40), it is tempting to speculate that PKD3 signaling may stabilize p63 in proliferative KCs through negative regulation of GSK3.…”

Section: Discussionmentioning

confidence: 99%

Opposing Growth Regulatory Roles of Protein Kinase D Isoforms in Human Keratinocytes

Ryvkin

Rashel

Gaddapara

et al. 2015

Journal of Biological Chemistry

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Background:The role of protein kinase D (PKD) signaling in human epidermis is unclear. Results: PKD isoforms have distinct and opposing growth regulatory functions in human keratinocytes. PKD3 is down-regulated upon differentiation and PKD3 silencing results in loss of keratinocyte proliferative potential. Conclusion: PKD signaling is essential for maintaining human epidermal homeostasis. Significance: PKD3 represents a potential drug target in hyperproliferative skin disorders.

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Section: Discussionmentioning

confidence: 99%

Opposing Growth Regulatory Roles of Protein Kinase D Isoforms in Human Keratinocytes

Ryvkin

Rashel

Gaddapara

et al. 2015

Journal of Biological Chemistry

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“…In response to several genotoxic agents, ubiquitylation and proteasomal degradation were shown to be prevented by phosphorylation on the TA isoforms (Rossi et al, 2006;Li et al, 2008;MacPartlin et al, 2008), whereas promoted also, by phosphorylation on the DN isoforms (Liefer et al, 2000;Westfall et al, 2005; HIPK2/DNp63a axis in DNA damage response C Lazzari et al Zangen et al, 2005). Though Y phosphorylation was overall shown to be associated to TA stability (Gonfloni et al, 2009;Wang et al, 2010) and S/T phosphorylation to DN degradation (Westfall et al, 2005;Huang et al, 2008;Galli et al, 2010), the molecular pathways underlying these divergent events and their balance have just begun to be described. The HIPK2 activity on DNp63a we are reporting here is consistent with the general idea that the cellular amount of this p63 isoform has to be reduced to enable an effective DDR.…”

Section: Discussionmentioning

confidence: 99%

“…A strong functional link between DNp63a phosphorylation and its subsequent degradation has been observed upon treatment with different genotoxic agents (Papoutsaki et al, 2005;Westfall et al, 2005;Huang et al, 2008;Galli et al, 2010). In addition, upon CDDP treatment, three specific phosphorylation sites (that is, S375, T397 and S466) have been identified in the C-terminal region of DNp63a by mass spectrometry (Huang et al, 2008; Figure 5c, underscored sites).…”

Section: Hipk2 Contributes To Tumor Cell Chemosensitivity Through P53mentioning

confidence: 93%

HIPK2 phosphorylates ΔNp63α and promotes its degradation in response to DNA damage

Lazzari¹,

Prodosmo²,

Siepi³

et al. 2011

Oncogene

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Homeodomain-interacting protein kinase 2 (HIPK2) is an emerging player in cell response to genotoxic agents that senses damage intensity and contributes to the cell's choice between cell cycle arrest and apoptosis. Phosphorylation of p53 at S46, an apoptosis-specific p53 posttranslational modification, is the most characterized HIPK2 function in response to lethal doses of ultraviolet (UV), ionizing radiation or different anticancer drugs, such as cisplatin, roscovitine and doxorubicin (DOX). Indeed, like p53, HIPK2 has been shown to contribute to the effectiveness of these treatments. Interestingly, p53-independent mechanisms of HIPK2-induced apoptosis were described for UV and tumor growth factor-b treatments; however, it is unknown whether these mechanisms are relevant for the responses to anticancer drugs. Because of the importance of the so-called 'p53-independent apoptosis and drug response' in human cancer chemotherapy, we asked whether p53-independent factor(s) might be involved in HIPK2-mediated chemosensitivity. Here, we show that HIPK2 depletion by RNA interference induces resistance to different anticancer drugs even in p53-null cells, suggesting the involvement of HIPK2 targets other than p53 in response to chemotherapy. In particular, we found that HIPK2 phosphorylates and promotes proteasomal degradation of DNp63a, a prosurvival DN isoform of the p53 family member, p63. Indeed, effective cell response to different genotoxic agents was shown to require phosphorylation-induced proteasomal degradation of DNp63a. In DOX-treated cells, we show that HIPK2 depletion interferes with DNp63a degradation, and expression of a HIPK2-resistant DNp63a-D390 mutant induces chemoresistance. We identify T397 as the DNp63a residue phosphorylated by HIPK2, and show that the nonphosphorylatable DNp63a-T397A mutant is not degraded in the face of either HIPK2 overexpression or DOX treatment. These results indicate DNp63a as a novel target of HIPK2 in response to genotoxic drugs.

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“…On the contrary, Calabro et al [54] showed that p63α and p63γ are able to associate with human Mdm2, and that Mdm2 is able to increase the steady-state level of p63 and enhance transcriptional activity under conditions in which p53 is inhibited. Most recently, Galli et al [55] have shown that Mdm2 induces p63 protein degradation following DNA damage and cell differentiation. They demonstrated that Mdm2 binds ΔNp63α in the nucleus, promoting its translocation to the cytoplasm, where it is targeted for degradation.…”

Section: Tp63 Gene and P63 Protein Isoformsmentioning

confidence: 99%

The role of P63 in cancer, stem cells and cancer stem cells

Nekulova

Holcakova

Coates

et al. 2011

Cellular and Molecular Biology Letters

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The transcription factor p63 has important functions in tumorigenesis, epidermal differentiation and stem cell self-renewal. The TP63 gene encodes multiple protein isoforms that have different or even antagonistic roles in these processes. The balance of p63 isoforms, together with the presence or absence of the other p53 family members, p73 and p53, has a striking biological impact. There is increasing evidence that interactions between p53-family members, whether cooperative or antagonistic, are involved in various cell processes. This review summarizes the current understanding of the role of p63 in tumorigenesis, metastasis, cell migration and senescence. In particular, recent data indicate important roles in adult stem cell and cancer stem cell regulation and in the response of cancer cells to therapy.

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MDM2 and Fbw7 cooperate to induce p63 protein degradation following DNA damage and cell differentiation

Cited by 92 publications

References 50 publications

Opposing Growth Regulatory Roles of Protein Kinase D Isoforms in Human Keratinocytes

Opposing Growth Regulatory Roles of Protein Kinase D Isoforms in Human Keratinocytes

HIPK2 phosphorylates ΔNp63α and promotes its degradation in response to DNA damage

The role of P63 in cancer, stem cells and cancer stem cells

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