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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)693-702
Number of pages10
JournalJournal of Clinical Investigation
Volume117
Issue number3
DOIs
Publication statusPublished - Mar 1 2007

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Homeodomain Proteins
Protein Kinases
Apoptosis
Gene Rearrangement
RNA Interference
Neoplasms
Cytoplasm
Breast Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

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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.

In: Journal of Clinical Investigation, Vol. 117, No. 3, 01.03.2007, p. 693-702.

Research output: Contribution to journalArticle

Pierantoni, Giovanna Maria ; Rinaldo, Cinzia ; Mottolese, Marcella ; Benedetto, Anna Di ; Esposito, Francesco ; Soddu, Silvia ; Fusco, Alfredo. / High-mobility group A1 inhibits p53 by cytoplasmic relocalization of its proapoptotic activator HIPK2. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 3. pp. 693-702.
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AU - Esposito, Francesco

AU - Soddu, Silvia

AU - Fusco, Alfredo

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