title: Pcif1 modulates Pdx1 protein stability and pancreatic β cell function and survival in mice.
abstract: The homeodomain transcription factor pancreatic duodenal homeobox 1 (Pdx1) is a major mediator of insulin transcription and a key regulator of the β cell phenotype. Heterozygous mutations in PDX1 are associated with the development of diabetes in humans. Understanding how Pdx1 expression levels are controlled is therefore of intense interest in the study and treatment of diabetes. Pdx1 C terminus-interacting factor-1 (Pcif1, also known as SPOP) is a nuclear protein that inhibits Pdx1 transactivation. Here, we show that Pcif1 targets Pdx1 for ubiquitination and proteasomal degradation. Silencing of Pcif1 increased Pdx1 protein levels in cultured mouse β cells, and Pcif1 heterozygosity normalized Pdx1 protein levels in Pdx1(+/-) mouse islets, thereby increasing expression of key Pdx1 transcriptional targets. Remarkably, Pcif1 heterozygosity improved glucose homeostasis and β cell function and normalized β cell mass in Pdx1(+/-) mice by modulating β cell survival. These findings indicate that in adult mouse β cells, Pcif1 limits Pdx1 protein accumulation and thus the expression of insulin and other gene targets important in the maintenance of β cell mass and function. They also provide evidence that targeting the turnover of a pancreatic transcription factor in vivo can improve glucose homeostasis.
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Claiborn
authors.forename: Mira M
authors.initials: MM
authors.lastname: Sachdeva
authors.forename: Corey E
authors.initials: CE
authors.lastname: Cannon
authors.forename: David N
authors.initials: DN
authors.lastname: Groff
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Singer
authors.forename: Doris A
authors.initials: DA
authors.lastname: Stoffers
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D044842:Cullin Proteins / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D018398:Homeodomain Proteins / Q000032:analysis / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism*; D043743:Ubiquitin-Protein Ligase Complexes; D054875:Ubiquitination
chemical_list: C503646:Cul3 protein, mouse; D044842:Cullin Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; C509762:Spop protein, mouse; D043743:Ubiquitin-Protein Ligase Complexes; D005947:Glucose
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