Mutations of HNF-1β inhibit epithelial morphogenesis through dysregulation of SOCS-3

Zhendong Ma, Yimei Gong, Vishal Patel, Courtney M. Karner, Evelyne Fischer, Thomas Hiesberger, Thomas J. Carroll, Marco Pontoglio, Peter Igarashi

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Hepatocyte nuclear factor-1β (HNF-1β) is a Pit-1, Oct-1/2, Unc-86 (POU) homeodomain-containing transcription factor expressed in the kidney, liver, pancreas, and other epithelial organs. Mutations of HNF-1β cause maturity-onset diabetes of the young, type 5 (MODY5), which is characterized by early-onset diabetes mellitus and congenital malformations of the kidney, pancreas, and genital tract. Knockout of HNF-1β in the mouse kidney results in cyst formation. However, the signaling pathways and transcriptional programs controlled by HNF-1β are poorly understood. Using genome-wide chromatin immunoprecipitation and DNA microarray (ChIP-chip) and microarray analysis of mRNA expression, we identified SOCS3 (suppressor of cytokine signaling-3) as a previously unrecognized target gene of HNF-1β in the kidney. HNF-1β binds to the SOCS3 promoter and represses SOCS3 transcription. The expression of SOCS3 is increased in HNF-1β knockout mice and in renal epithelial cells expressing dominant-negative mutant HNF-1β. Increased levels of SOCS-3 inhibit HGF-induced tubulogenesis by decreasing phosphorylation of Erk and STAT-3. Conversely, knockdown of SOCS-3 in renal epithelial cells expressing dominantnegative mutant HNF-1β rescues the defect in HGF-induced tubulogenesis by restoring phosphorylation of Erk and STAT-3. Thus, HNF-1β regulates tubulogenesis by controlling the levels of SOCS-3 expression. Manipulating the levels of SOCS-3 may be a useful therapeutic approach for human diseases induced by HNF-1β mutations.

Original languageEnglish (US)
Pages (from-to)20386-20391
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number51
DOIs
StatePublished - Dec 18 2007

Fingerprint

Hepatocyte Nuclear Factor 1
Morphogenesis
Mutation
Kidney
Cytokines
Pancreas
Epithelial Cells
Phosphorylation
Chromatin Immunoprecipitation
Microarray Analysis
Oligonucleotide Array Sequence Analysis
Knockout Mice

Keywords

  • Chromatin
  • Kidney
  • TCF2
  • Transcription
  • Tubulogenesis

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Mutations of HNF-1β inhibit epithelial morphogenesis through dysregulation of SOCS-3. / Ma, Zhendong; Gong, Yimei; Patel, Vishal; Karner, Courtney M.; Fischer, Evelyne; Hiesberger, Thomas; Carroll, Thomas J.; Pontoglio, Marco; Igarashi, Peter.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 51, 18.12.2007, p. 20386-20391.

Research output: Contribution to journalArticle

Ma, Zhendong ; Gong, Yimei ; Patel, Vishal ; Karner, Courtney M. ; Fischer, Evelyne ; Hiesberger, Thomas ; Carroll, Thomas J. ; Pontoglio, Marco ; Igarashi, Peter. / Mutations of HNF-1β inhibit epithelial morphogenesis through dysregulation of SOCS-3. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 51. pp. 20386-20391.
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AU - Ma, Zhendong

AU - Gong, Yimei

AU - Patel, Vishal

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AU - Fischer, Evelyne

AU - Hiesberger, Thomas

AU - Carroll, Thomas J.

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AB - Hepatocyte nuclear factor-1β (HNF-1β) is a Pit-1, Oct-1/2, Unc-86 (POU) homeodomain-containing transcription factor expressed in the kidney, liver, pancreas, and other epithelial organs. Mutations of HNF-1β cause maturity-onset diabetes of the young, type 5 (MODY5), which is characterized by early-onset diabetes mellitus and congenital malformations of the kidney, pancreas, and genital tract. Knockout of HNF-1β in the mouse kidney results in cyst formation. However, the signaling pathways and transcriptional programs controlled by HNF-1β are poorly understood. Using genome-wide chromatin immunoprecipitation and DNA microarray (ChIP-chip) and microarray analysis of mRNA expression, we identified SOCS3 (suppressor of cytokine signaling-3) as a previously unrecognized target gene of HNF-1β in the kidney. HNF-1β binds to the SOCS3 promoter and represses SOCS3 transcription. The expression of SOCS3 is increased in HNF-1β knockout mice and in renal epithelial cells expressing dominant-negative mutant HNF-1β. Increased levels of SOCS-3 inhibit HGF-induced tubulogenesis by decreasing phosphorylation of Erk and STAT-3. Conversely, knockdown of SOCS-3 in renal epithelial cells expressing dominantnegative mutant HNF-1β rescues the defect in HGF-induced tubulogenesis by restoring phosphorylation of Erk and STAT-3. Thus, HNF-1β regulates tubulogenesis by controlling the levels of SOCS-3 expression. Manipulating the levels of SOCS-3 may be a useful therapeutic approach for human diseases induced by HNF-1β mutations.

KW - Chromatin

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KW - TCF2

KW - Transcription

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