The HNF1β transcription factor has several domains involved in nephrogenesis and partially rescues Pax8/lim1‐induced kidney malformations

Abstract

The tissue-specific transcription factors HNF1alpha and HNF1beta are closely related homeodomain proteins conserved in vertebrate evolution. Heterozygous mutations in human HNF1beta but not in HNF1alpha genes are associated with kidney malformations. Overexpression of HNF1beta in Xenopus embryos leads to defective pronephros development, while HNF1alpha has no effect. We have defined the regions responsible for this functional difference between HNF1beta and HNF1alpha in transfected HeLa cells as well as in injected Xenopus embryos. Using domain swapping experiments, we located a nuclear localization signal in the POUH domain of HNF1beta, and showed that the POUS and POUH domains of HNF1beta mediate a high transactivation potential in transfected cells. In injected Xenopus embryos three HNF1beta domains are involved in nephrogenesis. These include the dimerization domain, the 26 amino acid segment specific for splice variant A as well as the POUH domain. As HNF1beta together with Pax8 and lim1 constitute the earliest regulators in the pronephric anlage, it is possible that they cooperate during early nephrogenesis. We have shown here that HNF1beta can overcome the enlargement and the induction of an ectopic pronephros mediated by overexpression of Pax8 and lim1. However, the phenotype induced by Pax8 and lim1 overexpression and characterized by cyst-like structures and thickening of the pronephric tubules was not altered by HNF1beta overexpression. Taken together, HNF1beta acts antagonistically to Pax8 and lim1 in only some processes during nephrogenesis, and a simple antagonistic relationship does not completely describe the functions of these genes. We conclude that HNF1beta has some distinct morphogenetic properties during nephrogenesis.

Genetic and functional analyses implicate the NUDT11 , HNF1B , and SLC22A3 genes in prostate cancer pathogenesis

“…In addition, turnover of diphosphoinositol polyphosphates in ovarian carcinoma cells affects apoptotic processes (30). HNF1B is a transcription factor that plays a role in kidney and pancreas development (31,32). Mutations of HNF1B have been described in renal cell carcinoma (33), and epigenetic silencing of the gene has been reported in ovarian cancer, as well as gastric, pancreatic, and colorectal cell lines (34).…”

A Systematic Review of Replication Studies of Prostate Cancer Susceptibility Genetic Variants in High-Risk Men Originally Identified from Genome-Wide Association Studies

“…However, the NUDT11 gene has not been described as having functional significance in prostate cancer. rs4430796 located in the HFN1B gene, is involved in organ development and regulation of the expression of multiple genes (46,47). Marker rs1859962 lies within a strong LD block within 17q24.3, the functional significance of which is unclear (27).…”

Hepatocyte nuclear factor 1β controls nephron tubular development

“…The study of animal models for Hnf1b deficiency in renal development and maturation has helped us to understand some of the functions of HNF1β (Bohn et al, 2003;Gresh et al, 2004;Hiesberger et al, 2004;Lokmane et al, 2010;Sun et al, 2004;Verdeguer et al, 2010;Wu et al, 2004). The phenotype of mice lacking Hnf1b depends very much on exactly when (developmental timing) and where (which tissue compartment) the gene is inactivated.…”