MDM2-Regulated Degradation of HIPK2 Prevents p53Ser46 Phosphorylation and DNA Damage-Induced Apoptosis

Rinaldo, Cinzia; Prodosmo, Andrea; Mancini, Francesca; Iacovelli, Stefano; Sacchi, Ada; Moretti, Fabiola; Soddu, Silvia

doi:10.1016/j.molcel.2007.02.008

Cited by 159 publications

(188 citation statements)

References 44 publications

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“…As for WSB-1 and Siah-2, Siah-1 depletion by siRNA partially inhibits hypoxia-induced HIPK2 degradation (Moehlenbrink et al, 2010). Interestingly, the p53-inducible Siah-1L protein downregulates HIPK2, suggesting an autoregulatory control of p53 response during hypoxia (Calzado et al, 2009b) similarly to that observed in MDM2 induction after nonsevere DNA damage (Rinaldo et al, 2007b) (Figure 5). In agreement, hypoxic condition by either low oxygen or chemical compound that mimics hypoxia (that is, cobalt chloride) induces p53-target MDM2 that promotes HIPK2 degradation.…”

Section: Hipk2 Inactivation In Tumors and P53 Dysfunctionmentioning

confidence: 65%

“…In response to nonsevere DNA damage, HIPK2 is required for PCAF-mediated acetylation of p53 at Lys320 and for p53-induced transcription of the cell cycle inhibitor p21 Waf1 (Di Stefano et al, 2005b). As nonsevere DNA damage also induces MDM2 for HIPK2 proteasomal degradation (Rinaldo et al, 2007b), altogether these findings suggest that different degree of DNA damage can activate HIPK2 and subsequently induce p53 posttranslational modifications to fine-tune p53 transcriptional activity and control cell life or death.…”

Section: Role Of Hipk2 In P53 Acetylationmentioning

confidence: 87%

“…MDM2 is not only a p53 inhibitor but also contributes to modulate the p53-mediated biological outcomes (that is, cell-cycle arrest versus apoptosis) to diverse triggering signals by regulating HIPK2. In response to nonlethal, presumably reparable DNA damage, p53-activated MDM2 inhibits the p53 apoptotic pathway by targeting HIPK2 at residue Lys1182 for proteasomal degradation (Rinaldo et al, 2007b). This suggest that MDM2 does not serve only as a p53 antagonist, rather, it can sometimes have an important role downstream of p53, helping it to adjust the biological outcome to the nature of the triggering signal (Shmueli and Oren, 2007).…”

Section: Interaction Between Hipk2 P53 and Mdm2mentioning

confidence: 99%

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Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

et al. 2010

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The p53 protein is the most studied tumor suppressor and the p53 pathway has been shown to mediate cellular stress responses that are disrupted when cancer develops. After DNA damage, p53 is activated as transcription factor to directly induce the expression of target genes involved in cell-cycle arrest, DNA repair, senescence and, importantly, apoptosis. Post-translational modifications of p53 are essential for the activation of p53 and for selection of target genes. The tumor suppressor homeodomain-interacting protein kinase-2 (HIPK2) is a crucial regulator of p53 apoptotic function by phosphorylating its N-terminal serine 46 (Ser46) and facilitating Lys382 acetylation at the C-terminus. HIPK2 is activated by numerous genotoxic agents and can be deregulated in tumors by several conditions including hypoxia. Recent findings suggest that HIPK2 active/inactive protein can affect p53 function in multiple and unexpected ways. This makes p53 as well as HIPK2 interesting targets for cancer therapy. Hence, understanding the role of HIPK2 as p53 activator may provide important insights in the process of tumor progression, and may also serve as the crucial point in the diagnostic and therapeutical aspects of cancer.

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Section: Hipk2 Inactivation In Tumors and P53 Dysfunctionmentioning

confidence: 65%

Section: Role Of Hipk2 In P53 Acetylationmentioning

confidence: 87%

Section: Interaction Between Hipk2 P53 and Mdm2mentioning

confidence: 99%

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Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

et al. 2010

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“…The region of HIPK2 that interacts with ZBTB4 contains the PEST domain, the adjacent autoinhibitory region (Rui et al, 2004) and a destabilization motif (Rinaldo et al, 2007a). This finding has four consequences: First, this portion of HIPK2 also interacts with other proteins, including p53 (Rinaldo et al, 2007b).…”

Section: Discussionmentioning

confidence: 99%

The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4

et al. 2009

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HIPK2 is a eukaryotic Serine-Threonine kinase that controls cellular proliferation and survival in response to exogenous signals. Here, we show that the human transcription factor ZBTB4 is a new target of HIPK2. The two proteins interact in vitro, colocalize and associate in vivo, and HIPK2 phosphorylates several conserved residues of ZBTB4. Overexpressing HIPK2 causes the degradation of ZBTB4, whereas overexpressing a kinasedeficient mutant of HIPK2 has no effect. The chemical activation of HIPK2 also decreases the amount of ZBTB4 in cells. Conversely, the inhibition of HIPK2 by drugs or by RNA interference causes a large increase in ZBTB4 levels. This negative regulation of ZBTB4 by HIPK2 occurs under normal conditions of cell growth. In addition, the degradation is increased by DNA damage. These findings have two consequences. First, we have recently shown that ZBTB4 inhibits the transcription of p21. Therefore, the activation of p21 by HIPK2 is twopronged: stimulation of the activator p53, and simultaneous repression of the inhibitor ZBTB4. Second, ZBTB4 is also known to bind methylated DNA and repress methylated sequences. Consequently, our findings raise the possibility that HIPK2 might influence the epigenetic regulation of gene expression at loci that remain to be identified.

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“…In unstressed cells, HIPK2 is complexed with and degraded by Siah-1, whereas in lethally DNAdamaged cells, Siah-1 becomes phosphorylated by ATM/ATR and dissociates from HIPK2 (Winter et al, 2008). In the case of Mdm2, it is increased in sublethally damaged cells due to p53 activation and degrades HIPK2; in lethally damaged cells, Mdm2 protein is present at much lower levels, such that HIPK2 remains stable (Rinaldo et al, 2007). Of note, it has also been reported that HIPK2 may cause apoptosis in a p53-independent manner through downregulating the transcriptional co-repressor CtBP (Zhang et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

AXIN is an essential co-activator for the promyelocytic leukemia protein in p53 activation

Wei

et al. 2010

Oncogene

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The PML protein is best known for its role as a tumor suppressor for acute promyelocytic leukemia. Both PML and the key Wnt signaling regulator AXIN regulate p53-dependent apoptosis in response to DNA damage. However, how the two major tumor suppressors coordinate with each other is unknown, and the molecular components orchestrating the PML-induced apoptosis remain enigmatic. Here we show that AXIN interacts with PML in vivo, and further that AXIN, PML and p53 form a ternary complex. Exposure to genotoxic signals including UV and doxorubicin induces AXIN to enter into the nucleus where it colocalizes with PML in the nuclear bodies. Domain-mapping experiments revealed that the C-terminal region (aa 597-832) of AXIN is responsible for its interaction with PML. AXIN fails to activate p53 in PML À/À cells, and conversely, PML is unable to activate p53 in AXIN-null SNU475 cells. Consistently, knockdown with respective siRNAs revealed that AXIN and PML depend on each other to elevate p53-Ser-46 phosphorylation and to induce apoptosis after treatment with genotoxins. Moreover, we found that dominantnegative mutants of PML blocked AXIN-induced p53 activation, and that AXIN promotes PML sumoylation, a modification necessary for PML functions. Our finding has thus provided a new avenue for understanding the mechanism by which PML activates p53 and exerts its role as a tumor suppressor.

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MDM2-Regulated Degradation of HIPK2 Prevents p53Ser46 Phosphorylation and DNA Damage-Induced Apoptosis

Cited by 159 publications

References 44 publications

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4

AXIN is an essential co-activator for the promyelocytic leukemia protein in p53 activation

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