Mutations of HNF-1beta inhibit epithelial morphogenesis through dysregulation of SOCS-3.
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.
Ma
Zhendong
Z
Departments of Internal Medicine, Molecular Biology, and Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Gong
Yimei
Y
Patel
Vishal
V
Karner
Courtney M
CM
Fischer
Evelyne
E
Hiesberger
Thomas
T
Carroll
Thomas J
TJ
Pontoglio
Marco
M
Igarashi
Peter
P
D000818:Animals; D047369:Chromatin Immunoprecipitation; D004847:Epithelial Cells / Q000502:physiology; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000502:physiology*; D007684:Kidney Tubules / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009024:Morphogenesis / Q000235:genetics*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051539:Hepatocyte Nuclear Factor 1-beta