High-mobility group A1 inhibits p53 by cytoplasmic relocalization of its proapoptotic activator HIPK2
Giovanna Maria Pierantoni, Cinzia Rinaldo, Marcella Mottolese, Anna Di Benedetto, Francesco Esposito, Silvia Soddu, Alfredo Fusco
Giovanna Maria Pierantoni, Cinzia Rinaldo, Marcella Mottolese, Anna Di Benedetto, Francesco Esposito, Silvia Soddu, Alfredo Fusco
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Research Article Oncology

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

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 4

HIPK2 is required for HMGA-mediated repression of apoptosis.

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HIPK2 is required for HMGA-mediated repression of apoptosis. (A) Western...
(A) Western blot analysis of endogenous HIPK2 in p53-null H1299 cells stably transfected with pSUPER-lacZ (β-Gali) or pSUPER-HIPK2 (HIPK2i) vectors. Heat shock protein 70 (Hsp70) was used as loading control. (B) The same cells used in A were infected with Adp53 and transfected with the pCEFL-Hmga1 vector or pCEFL empty vector. Cell death was measured as in Figure 2B, while TCEs from the same cells used in B were analyzed by Western blot as in Figure 2B for the indicated proteins. (C) Western blot analysis of endogenous HIPK2 in WT p53–expressing RKO cells stably transfected as in A. (D) The same cells used in C were transfected with HMGA1 and irradiated with UV light (50 J/m2) to activate the endogenous p53. The apoptotic index was calculated by TUNEL assay.