Two conserved domains in PCIF1 mediate interaction with pancreatic transcription factor PDX-1.
PCIF1 is a TRAF and POZ domain containing nuclear factor that interacts with and inhibits transactivation of pancreatic homeodomain transcription factor PDX-1. Here, we demonstrate interaction of endogenous PDX-1 and PCIF1 in MIN6 insulinoma cells. Within PCIF1, the TRAF and POZ domains are both required for physical and functional interaction with the C-terminus of PDX-1, whereas the C-terminal domain of PCIF1 directs its nuclear localization. A human PDX-1 mutation associated with diabetes, E224K, disrupts the ability of PCIF1 to inhibit PDX-1 transactivation, suggesting that the interaction between PDX-1 and PCIF1 is required for normal glucose homeostasis. Inhibition of transactivation occurs by a mechanism distinct from the classical role of POZ domains to recruit co-repressors and histone deacetylases. Understanding the functional roles of PCIF1 domains may have application to therapeutic beta-cell replacement strategies involving PDX-1 for the treatment of diabetes.
Liu
Aihua
A
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, and the Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Oliver-Krasinski
Jennifer
J
Stoffers
Doris A
DA
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D017124:Conserved Sequence; D019143:Evolution, Molecular; D005973:Glutamine / Q000235:genetics; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D043743:Ubiquitin-Protein Ligase Complexes; D015027:Zebrafish
D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; D005973:Glutamine; C509762:Spop protein, mouse; D043743:Ubiquitin-Protein Ligase Complexes; D008239:Lysine