Pcif1 modulates Pdx1 protein stability and pancreatic β cell function and survival in mice.
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.
Claiborn
Kathryn C
KC
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.
Sachdeva
Mira M
MM
Cannon
Corey E
CE
Groff
David N
DN
Singer
Jeffrey D
JD
Stoffers
Doris A
DA
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
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
Development. 1996 Mar;122(3):983-95
8631275
Mol Endocrinol. 2004 Mar;18(3):533-48
14701942
J Biol Chem. 2010 Jan 29;285(5):3406-16
19833727
Nature. 2002 Apr 18;416(6882):703-9
11961546
Nat Genet. 1997 Jan;15(1):106-10
8988180
FEBS Lett. 2006 Dec 11;580(28-29):6701-6
17126328
Genes Dev. 2006 Jan 15;20(2):253-66
16418487
Mol Cell Biol. 2006 Aug;26(15):5735-43
16847327
J Biol Chem. 2002 Mar 29;277(13):11225-32
11781323
Development. 1996 May;122(5):1409-16
8625829
J Biol Chem. 1996 Jan 26;271(4):2294-9
8567692
Proc Natl Acad Sci U S A. 2005 May 24;102(21):7635-40
15897469
Dev Biol. 2006 Oct 15;298(2):616-31
16962573
Nature. 1994 Oct 13;371(6498):606-9
7935793
J Biol Chem. 2006 Mar 10;281(10):6395-403
16407209
Nature. 2003 Sep 18;425(6955):316-21
13679922
Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19090-5
19855005
FEBS Lett. 1998 Jul 24;431(3):362-6
9714543
J Clin Invest. 2004 Sep;114(6):828-36
15372107
Am J Physiol Endocrinol Metab. 2003 Apr;284(4):E830-40
12488243
J Clin Invest. 1998 Jul 1;102(1):232-41
9649577
Nature. 2003 Sep 18;425(6955):311-6
13679921
J Biol Chem. 2005 Nov 18;280(46):38203-10
16166097
Dev Biol. 2005 Oct 1;286(1):225-37
16126192
J Biol Chem. 2000 Feb 4;275(5):3485-92
10652343
J Biol Chem. 2006 May 5;281(18):12664-72
16524876
Genes Dev. 2008 Dec 15;22(24):3435-48
19141476
Genes Dev. 2009 Apr 15;23(8):975-85
19390090
J Clin Invest. 2003 Apr;111(8):1147-60
12697734
J Clin Invest. 2009 Jul;119(7):1888-98
19487809
J Biol Chem. 2008 Mar 28;283(13):8678-86
18218622
Genes Dev. 1998 Jun 15;12(12):1763-8
9637677
Nat Cell Biol. 2003 Nov;5(11):950-1
14593416
Diabetes. 2005 Sep;54(9):2586-95
16123346
Mol Cell Biol. 1997 May;17(5):2598-604
9111329
J Clin Invest. 1999 Nov;104(9):R41-8
10545531
Mol Cell Biol. 2004 May;24(10):4372-83
15121856
Nat Genet. 1997 Oct;17(2):138-9
9326926
Am J Physiol Endocrinol Metab. 2005 Apr;288(4):E707-14
15562255
Genes Dev. 2009 Apr 15;23(8):906-11
19390085
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12236-41
12221286
Mol Genet Metab. 2007 Sep-Oct;92(1-2):43-55
17659992
Dev Cell. 2006 Jun;10(6):719-29
16740475