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

Abstract

Hepatocyte nuclear factor-1beta (HNF-1beta) 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-1beta 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-1beta in the mouse kidney results in cyst formation. However, the signaling pathways and transcriptional programs controlled by HNF-1beta 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-1beta in the kidney. HNF-1beta binds to the SOCS3 promoter and represses SOCS3 transcription. The expression of SOCS3 is increased in HNF-1beta knockout mice and in renal epithelial cells expressing dominant-negative mutant HNF-1beta. 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 dominant-negative mutant HNF-1beta rescues the defect in HGF-induced tubulogenesis by restoring phosphorylation of Erk and STAT-3. Thus, HNF-1beta 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-1beta mutations.

• Authors: Zhendong Ma, Yimei Gong, Vishal Patel, Courtney M Karner, Evelyne Fischer, Thomas Hiesberger, Thomas J Carroll, Marco Pontoglio, Peter Igarashi
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 51 Pg. 20386-91 (Dec 18 2007) ISSN: 1091-6490 [Electronic] United States
• PMID: 18077349 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Socs3 protein, mouse
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins
• Hepatocyte Nuclear Factor 1-beta

Topics

• Animals
• Chromatin Immunoprecipitation
• Epithelial Cells (physiology)
• Hepatocyte Nuclear Factor 1-beta (genetics, physiology)
• Kidney Tubules (growth & development, metabolism)
• Mice
• Mice, Knockout
• Mice, Mutant Strains
• Morphogenesis (genetics)
• Mutation
• Oligonucleotide Array Sequence Analysis
• Promoter Regions, Genetic
• RNA, Messenger (analysis, metabolism)
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (antagonists & inhibitors, genetics, metabolism)