Identification of PCIF1, a POZ domain protein that inhibits PDX-1 (MODY4) transcriptional activity.
Hox factors are evolutionarily conserved homeodomain-containing transcription factors that activate and repress gene expression in a precise temporally and spatially regulated manner during development and differentiation. Pancreatic-duodenal homeobox 1 (PDX-1) is a Hox-type protein that is a critical requirement for normal pancreas development and for proper differentiation of the endocrine pancreas. In humans, PDX-1 gene mutation causes pancreatic agenesis and early- and late-onset type 2 diabetes. PDX-1 consists of an N-terminal transactivation domain, a homeodomain responsible for DNA binding and nuclear localization, and a conserved C terminus that is mutated in human diabetes but whose function is poorly understood. We have identified a novel POZ domain protein, PDX-1 C terminus-interacting factor 1 (PCIF1)/SPOP, that interacts with PDX-1 both in vitro and in vivo. PCIF1 is localized to the nucleus in a speckled pattern, and coexpression of PDX-1 alters the subnuclear distribution of PCIF1. Functionally, PCIF1 inhibits PDX-1 transactivation of established target gene promoters in a specific and dose-dependent manner that requires critical amino acids in the PDX-1 C terminus. PCIF1 is expressed in adult pancreatic insulin-producing beta cells, and overexpression of PCIF1 inhibits the rat insulin 1 and rat insulin 2 promoters in the MIN6 insulinoma beta cell line. The coexpression of PCIF1 with PDX-1 in beta cells and the ability of PCIF1 to repress PDX-1 transactivation suggest that modulation of PDX-1 function by PCIF1 may regulate normal beta cell differentiation.
Liu
Aihua
A
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, and Penn Diabetes Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Desai
Biva M
BM
Stoffers
Doris A
DA
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D006367:HeLa Cells; D018398:Homeodomain Proteins; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; D007328:Insulin; D009687:Nuclear Proteins; C472862:PCIF1 protein, human; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D004247:DNA