High-mobility group A1 inhibits p53 by cytoplasmic relocalization of its proapoptotic activator HIPK2.
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.
Pierantoni
Giovanna Maria
GM
Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli Federico II, Naples, Italy.
Rinaldo
Cinzia
C
Mottolese
Marcella
M
Di Benedetto
Anna
A
Esposito
Francesco
F
Soddu
Silvia
S
Fusco
Alfredo
A
D017209:Apoptosis / Q000235:genetics*; D001943:Breast Neoplasms / Q000737:chemistry / Q000378:metabolism; D002277:Carcinoma / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002467:Cell Nucleus / Q000737:chemistry; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D005786:Gene Expression Regulation; D025741:HMGA1a Protein / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
D002352:Carrier Proteins; D016159:Tumor Suppressor Protein p53; D025741:HMGA1a Protein; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases