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High-mobility group A1 inhibits p53 by cytoplasmic relocalization of its proapoptotic activator HIPK2
Giovanna Maria Pierantoni, … , Silvia Soddu, Alfredo Fusco
Giovanna Maria Pierantoni, … , Silvia Soddu, Alfredo Fusco
Published March 1, 2007
Citation Information: J Clin Invest. 2007;117(3):693-702. https://doi.org/10.1172/JCI29852.
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Research Article Oncology

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

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Abstract

High-mobility group A1 (HMGA1) overexpression and gene rearrangement are frequent events in human cancer, but the molecular basis of HMGA1 oncogenic activity remains unclear. Here we describe a mechanism through which HMGA1 inhibits p53-mediated apoptosis by counteracting the p53 proapoptotic activator homeodomain-interacting protein kinase 2 (HIPK2). We found that HMGA1 overexpression promoted HIPK2 relocalization in the cytoplasm and inhibition of p53 apoptotic function, while HIPK2 overexpression reestablished HIPK2 nuclear localization and sensitivity to apoptosis. HIPK2 depletion by RNA interference suppressed the antiapoptotic effect of HMGA1, which indicates that HIPK2 is the target required for HMGA1 to repress the apoptotic activity of p53. Consistent with this process, a strong correlation among HMGA1 overexpression, HIPK2 cytoplasmic localization, and low spontaneous apoptosis index (comparable to that observed in mutant p53–carrying tumors) was observed in WT p53–expressing human breast carcinomas. Hence, cytoplasmic relocalization of HIPK2 induced by HMGA1 overexpression is a mechanism of inactivation of p53 apoptotic function that we believe to be novel.

Authors

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

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Figure 1

HMGA1, p53, and HIPK2 coexpression activates proapoptotic genes.

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HMGA1, p53, and HIPK2 coexpression activates proapoptotic genes.
Effect ...
Effect of FLAG-tagged WT HIPK2 or the kinase-defective HIPK2 mutant (FLAG-K221R/HIPK2) on the activity exerted by HMGA1 on reporter vectors mdm2 (A), bax (B), p21waf1 (C), and PIG3 (D). p53-null H1299 cells were used as recipient. The pCMV-p53 vector encoding WT p53 protein was transfected alone or with the indicated plasmids. All transfections were performed in duplicate; data are mean ± SD of 5 independent experiments. Empty vectors were used as a control. Western blot analyses of p53, HMGA1, and FLAG-HIPK2 proteins expression from 1 indicative experiment are shown in the lower panels.
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