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PMID: 12488434 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth.

The Journal of clinical investigation ·Vol. 110 ·No. 12 ·2002-12-00 ·Pages 1839-47

Kitamura T, Nakae J, Kitamura Y, Kido Y, Biggs WH, Wright CV, White MF, Arden KC, Accili D

Abstract

Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing beta cells. The mechanisms governing replication of terminally differentiated beta cells and neogenesis from progenitor cells are unclear. Mice lacking insulin receptor substrate-2 (Irs2) develop beta cell failure, suggesting that insulin signaling is required to maintain an adequate beta cell mass. We report that haploinsufficiency for the forkhead transcription factor Foxo1 reverses beta cell failure in Irs2(-/-) mice through partial restoration of beta cell proliferation and increased expression of the pancreatic transcription factor pancreas/duodenum homeobox gene-1 (Pdx1). Foxo1 and Pdx1 exhibit mutually exclusive patterns of nuclear localization in beta cells, and constitutive nuclear expression of a mutant Foxo1 is associated with lack of Pdx1 expression. We show that Foxo1 acts as a repressor of Foxa2-dependent (Hnf-3beta-dependent) expression from the Pdx1 promoter. We propose that insulin/IGFs regulate beta cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset of cells embedded within pancreatic ducts.

MeSH Terms
Animals Cell Line Cell Nucleus/metabolism Diabetes Mellitus, Type 2/metabolism Epithelial Cells/cytology,metabolism Forkhead Box Protein O1 Forkhead Transcription Factors Genes, Reporter Homeodomain Proteins Humans Insulin/metabolism Insulin Receptor Substrate Proteins Intracellular Signaling Peptides and Proteins Islets of Langerhans/cytology,growth & development Kidney/cytology Mice Mice, Knockout Microscopy, Fluorescence Pancreas/cytology,metabolism Phosphoproteins/genetics,metabolism Promoter Regions, Genetic Protein Isoforms Receptor, Insulin/genetics,metabolism Signal Transduction/physiology Trans-Activators/genetics,metabolism Transcription Factors/genetics,metabolism
Chemicals
Forkhead Box Protein O1 Forkhead Transcription Factors Foxo1 protein, mouse Homeodomain Proteins IRS2 protein, human Insulin Insulin Receptor Substrate Proteins Intracellular Signaling Peptides and Proteins Irs2 protein, mouse Phosphoproteins Protein Isoforms Trans-Activators Transcription Factors pancreatic and duodenal homeobox 1 protein Receptor, Insulin
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Kitamura Tadahiro
Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, New York, USA.
Nakae Jun
Kitamura Yukari
Kido Yoshiaki
Biggs William H
Wright Christopher V E
White Morris F
Arden Karen C
Accili Domenico
References (38)
38 references, click to expand
  1. Insulin signalling and the regulation of glucose and lipid metabolism.
    Nature. 2001 Dec 13;414(6865):799-806 PMID: 11742412
  2. Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling.
    Nat Genet. 1999 Sep;23(1):32-40 PMID: 10471495
  3. Pbx1 inactivation disrupts pancreas development and in Ipf1-deficient mice promotes diabetes mellitus.
    Nat Genet. 2002 Apr;30(4):430-5 PMID: 11912494
  4. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors.
    Development. 2002 May;129(10):2447-57 PMID: 11973276
  5. beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass.
    Nat Genet. 2002 May;31(1):111-5 PMID: 11923875
  6. Developmental expression of the homeodomain protein IDX-1 in mice transgenic for an IDX-1 promoter/lacZ transcriptional reporter.
    Endocrinology. 1999 Nov;140(11):5374-81 PMID: 10537169
  7. Cellular survival: a play in three Akts.
    Genes Dev. 1999 Nov 15;13(22):2905-27 PMID: 10579998
  8. Unified nomenclature for the winged helix/forkhead transcription factors.
    Genes Dev. 2000 Jan 15;14(2):142-6 PMID: 10702024
  9. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1.
    Nature. 2000 Apr 13;404(6779):782-7 PMID: 10783894
  10. In vitro cultivation of human islets from expanded ductal tissue.
    Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7999-8004 PMID: 10884429
  11. Functional conservation of regulatory elements in the pdx-1 gene: PDX-1 and hepatocyte nuclear factor 3beta transcription factors mediate beta-cell-specific expression.
    Mol Cell Biol. 2000 Oct;20(20):7583-90 PMID: 11003654
  12. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1.
    Curr Biol. 2000 Oct 5;10(19):1201-4 PMID: 11050388
  13. Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia.
    Diabetes. 2000 Nov;49(11):1880-9 PMID: 11078455
  14. Life and death of the pancreatic beta cells.
    Trends Endocrinol Metab. 2000 Nov;11(9):375-8 PMID: 11042468
  15. Association between islets of Langerhans and pancreatic ductal system in adult rat. Where endocrine and exocrine meet together?
    Diabetologia. 2001 May;44(5):575-84 PMID: 11380075
  16. Preserved pancreatic beta-cell development and function in mice lacking the insulin receptor-related receptor.
    Mol Cell Biol. 2001 Aug;21(16):5624-30 PMID: 11463843
  17. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression.
    J Clin Invest. 2001 Nov;108(9):1359-67 PMID: 11696581
  18. A kinase in the life of the beta cell.
    J Clin Invest. 2001 Dec;108(11):1575-6 PMID: 11733550
  19. Diabetes mellitus and genetically programmed defects in beta-cell function.
    Nature. 2001 Dec 13;414(6865):788-91 PMID: 11742410
  20. Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclear receptor-interacting protein with both coactivator and corepressor functions.
    J Biol Chem. 2001 Jul 27;276(30):27907-12 PMID: 11353774
  21. Regeneration of pancreatic beta cells from intra-islet precursor cells in an experimental model of diabetes.
    Endocrinology. 2001 Nov;142(11):4956-68 PMID: 11606464
  22. Pdx1 restores beta cell function in Irs2 knockout mice.
    J Clin Invest. 2002 May;109(9):1193-201 PMID: 11994408
  23. Foxa2 controls Pdx1 gene expression in pancreatic beta-cells in vivo.
    Diabetes. 2002 Aug;51(8):2546-51 PMID: 12145169
  24. Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1.
    Nat Genet. 2002 Oct;32(2):245-53 PMID: 12219087
  25. Defective insulin secretion in pancreatic beta cells lacking type 1 IGF receptor.
    J Clin Invest. 2002 Oct;110(7):1011-9 PMID: 12370279
  26. Islet cells as a component of pancreatic ductal neoplasms. I. Experimental study: ductular cells, including islet cell precursors, as primary progenitor cells of tumors.
    Am J Pathol. 1978 Feb;90(2):295-316 PMID: 341720
  27. Characterization of immunoreactive components of insulin and somatostatin in canine pancreatic juice.
    FEBS Lett. 1979 Sep 1;105(1):23-6 PMID: 488343
  28. The insulin-pancreatic acinar axis.
    Diabetes. 1985 Oct;34(10):980-6 PMID: 2412919
  29. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells.
    Nucleic Acids Res. 1989 Aug 11;17(15):6419 PMID: 2771659
  30. The IRS-2 gene on murine chromosome 8 encodes a unique signaling adapter for insulin and cytokine action.
    Mol Endocrinol. 1997 Feb;11(2):251-62 PMID: 9013772
  31. Hormonal regulation of an islet-specific enhancer in the pancreatic homeobox gene STF-1.
    Mol Cell Biol. 1997 May;17(5):2598-604 PMID: 9111329
  32. Insulin administration enhances growth of the beta-cell mass in streptozotocin-treated newborn rats.
    Diabetes. 1997 Sep;46(9):1445-52 PMID: 9287045
  33. Hepatocyte nuclear factor 3beta is involved in pancreatic beta-cell-specific transcription of the pdx-1 gene.
    Mol Cell Biol. 1997 Oct;17(10):6002-13 PMID: 9315659
  34. Disruption of IRS-2 causes type 2 diabetes in mice.
    Nature. 1998 Feb 26;391(6670):900-4 PMID: 9495343
  35. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes.
    Cell. 1999 Feb 5;96(3):329-39 PMID: 10025399
  36. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.
    Cell. 1999 Mar 19;96(6):857-68 PMID: 10102273
  37. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway.
    J Biol Chem. 1999 Jun 4;274(23):15982-5 PMID: 10347145
  38. Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion.
    J Biol Chem. 2002 Mar 29;277(13):11225-32 PMID: 11781323
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI16857
Published
2002-12-00
Pages
1839-47
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC151657
Subset
IM
Grants
NIDDK NIH HHS · R01 DK057539 · United States
NIDDK NIH HHS · DK-57539 · United States
External Links
PubMed source DOI: 10.1172/JCI16857 PMC Full Text View journal details
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