The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells

Article Article scientifique Article The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells eng 2007 author Brun Thierry 0000-0002-1659-4283 24644 author Duhamel Dominique 23185 author Hu He Kaihui 603945 author Wollheim Claes 25195 author Gauthier Benoît 129022 4261-4271 10.1038/sj.onc.1210205 17260022 0950-9232 The paired/homeodomain transcription factor Pax4 is essential for islet beta-cell generation during pancreas development and their survival in adulthood. High Pax4 expression was reported in human insulinomas indicating that deregulation of the gene may be associated with tumorigenesis. We report that rat insulinoma INS-1E cells express 25-fold higher Pax4 mRNA levels than rat islets. In contrast to primary beta-cells, activin A but not betacellulin or glucose induced Pax4 mRNA levels indicating dissociation of Pax4 expression from insulinoma cell proliferation. Short hairpin RNA adenoviral constructs targeted to the paired domain or homeodomain (viPax4PD and viPax4HD) were generated. Pax4 mRNA levels were lowered by 73 and 50% in cells expressing either viPax4PD or viPax4HD. Transcript levels of the Pax4 target gene bcl-xl were reduced by 53 and 47%, whereas Pax6 and Pdx1 mRNA levels were unchanged. viPax4PD-infected cells displayed a twofold increase in spontaneous apoptosis and were more susceptible to cytokine-induced cell death. In contrast, proliferation was unaltered. RNA interference-mediated repression of insulin had no adverse effects on either Pax4 or Pdx1 expression as well as on cell replication or apoptosis. These results indicate that Pax4 is redundant for proliferation of insulinoma cells, whereas it is essential for survival through upregulation of the antiapoptotic gene bcl-xl. Animals Apoptosis/genetics Apoptosis Regulatory Proteins/genetics/physiology Cell Division/genetics Cell Line, Tumor Cell Proliferation Cell Survival/genetics Homeodomain Proteins/genetics/physiology Insulinoma/genetics/metabolism/pathology Paired Box Transcription Factors/genetics/physiology RNA, Messenger/biosynthesis Rats Rats, Wistar Up-Regulation/genetics Bcl-X Protein/biosynthesis/genetics Dewey 612 134 Département de physiologie cellulaire et métabolisme 21C false Oncogene 26 29 e050bf48-0efd-47c8-9ba6-08285cb5eeab Article (Published version) Restricted Pax4.pdf 478693 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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The transcription factor PAX4 acts as a survival gene in INS-1E insulinoma cells	Oncogene			2007	668	0

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