High-mobility group A1 inhibits p53 by cytoplasmic relocalization of its proapoptotic activator HIPK2

Pierantoni, Giovanna Maria; Rinaldo, Cinzia; Mottolese, Marcella; Benedetto, Anna Di; Esposito, Francesco; Soddu, Silvia; Fusco, Alfredo

doi:10.1172/jci29852

Cited by 88 publications

(102 citation statements)

References 43 publications

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“…The data reported here suggest the hypothesis that HMGAs might enhance the cellular response to DNA damage, increasing ATM protein levels, and through their previously described anti-apoptotic activity (Pierantoni et al, 2007), could shift ATM signaling from cell death to cell survival and resistance to genotoxic drugs. However, further experiments are requested to be clearly confirmed and elucidated.…”

Section: Discussionsupporting

confidence: 60%

“…Conversely Hmga1 KO MEFs did not show a reduction in the p53/p21 pathway, while Hmga2 KO MEFs displayed reduced levels of p21 mRNA and p53ser15 compared with wild-type MEFs. The absence of Hmga1-dependent inhibition of p53 (Pierantoni et al, 2006;Pierantoni et al, 2007) may account for this difference between Hmga1 and Hmga2 single knock-out MEFs. Our results also indicate a key role for HMGA proteins in the cellular DDR.…”

Section: Discussionmentioning

confidence: 99%

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HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

et al. 2011

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DNA-damaging therapies represent a keystone in cancer treatment. Unfortunately, many tumors often relapse because of a group of cancer cells, which are resistant to conventional therapies. High-mobility group A (HMGA) proteins has a key role in cell transformation, and their overexpression is a common feature of human malignant neoplasias, representing a poor prognostic index often correlated to anti-cancer drug resistance. Our previous results demonstrated that HMGA1 is a substrate of ataxiatelangiectasia mutated (ATM), the main cellular sensor of genotoxic stress. Here we also report thatHMGA2, the other member of the HMGA family, is a novel substrate of ATM. Interestingly, we found that HMGA proteins positively regulate ATM gene expression. Moreover, induction of ATM kinase activity by DNA-damaging agents enhances HMGA-dependent transcriptional activation of ATM promoter, suggesting that ATM expression is modulated by a DNA-damage-and HMGA-dependent positive feedback loop. Finally, inhibition of HMGA expression in mouse embryonic fibroblasts and in cancer cells strongly reduces ATM protein levels, impairing the cellular DNA-damage response and enhancing the sensitivity to DNA-damaging agents. These findings indicate this novel HMGA-ATM pathway as a new potential target to improve the effectiveness of conventional anti-neoplastic treatments on the genotoxic-drug resistant cancer cells.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

et al. 2011

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“…HIPK2 cytoplasmic localization, similarly to what seen in the leukemogenesis model (Britos-Bray et al, 1998;Wee et al, 2008) (see above), was found related to high-mobility group A1 (HMGA1) overexpression leading to inhibition of p53-mediated apoptosis (Pierantoni et al, 2007). HMGA1 protein is frequently overexpressed in tumors and correlates strongly with cytoplasmic HIPK2 localization and low apoptotic index in wt p53-positive human breast cancer tissues (Pierantoni et al, 2007). These data strengthen the role of HIPK2 as p53 activator as well as biomarker for tumor progression even in the absence of p53 mutations.…”

Section: Hipk2 Inactivation In Tumors and P53 Dysfunctionsupporting

confidence: 67%

“…However, in that study, HIPK2 was found mutated in a very small percentage (2 out of 130 cases) so that it is difficult to justify a connection with p53 inactivation. HIPK2 cytoplasmic localization, similarly to what seen in the leukemogenesis model (Britos-Bray et al, 1998;Wee et al, 2008) (see above), was found related to high-mobility group A1 (HMGA1) overexpression leading to inhibition of p53-mediated apoptosis (Pierantoni et al, 2007). HMGA1 protein is frequently overexpressed in tumors and correlates strongly with cytoplasmic HIPK2 localization and low apoptotic index in wt p53-positive human breast cancer tissues (Pierantoni et al, 2007).…”

Section: Hipk2 Inactivation In Tumors and P53 Dysfunctionmentioning

confidence: 60%

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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“…The deletion of HIPK2 in mice is pleiotropic, but supports a role of the kinase in cell survival (Isono et al, 2006;Wei et al, 2007). In addition to regulating transcription factors, HIPK2 binds, phosphorylates and regulates the activity of the chromatin protein HMGA1 (Pierantoni et al, 2001(Pierantoni et al, , 2007Zhang and Wang, 2007), and it also acts on the Polycomb group protein Pc2 . The regulation of HMGA1 and Pc2 suggests that HIPK2 may also act at the level of epigenetic control.…”

Section: Introductionmentioning

confidence: 88%

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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High-mobility group A1 inhibits p53 by cytoplasmic relocalization of its proapoptotic activator HIPK2

Cited by 88 publications

References 43 publications

HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents

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

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