High-mobility group A1 proteins regulate p53-mediated transcription of Bcl-2 gene.
We have previously described a mechanism through which the high-mobility group A1 (HMGA1) proteins inhibit p53-mediated apoptosis by delocalizing the p53 proapoptotic activator homeodomain-interacting protein kinase 2 from the nucleus to the cytoplasm. By this mechanism, HMGA1 modulates the transcription of p53 target genes such as Mdm2, p21(waf1), and Bax, inhibiting apoptosis. Here, we report that HMGA1 antagonizes the p53-mediated transcriptional repression of another apoptosis-related gene, Bcl-2, suggesting a novel mechanism by which HMGA1 counteracts apoptosis. Moreover, HMGA1 overexpression promotes the reduction of Brn-3a binding to the Bcl-2 promoter, thereby blocking the Brn-3a corepressor function on Bcl-2 expression following p53 activation. Consistently, a significant direct correlation between HMGA1 and Bcl-2 overexpression has been observed in human breast carcinomas harboring wild-type p53. Therefore, this study suggests a novel mechanism, based on Bcl-2 induction, by which HMGA1 overexpression contributes to the escape from apoptosis leading to neoplastic transformation.
Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Università degli Studi di Napoli Federico II, Naples, Italy.
Francesco
F
Esposito
Mara
M
Tornincasa
Paolo
P
Chieffi
Ivana
I
De Martino
Giovanna Maria
GM
Pierantoni
Alfredo
A
Fusco
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2; D025741:HMGA1a Protein / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D050819:Transcription Factor Brn-3A / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D002352:Carrier Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D050819:Transcription Factor Brn-3A; D016159:Tumor Suppressor Protein p53; D025741:HMGA1a Protein; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases