scholarly journals Overexpression of dominant negative mutant hepatocyte nuclear factor (HNF)-1α inhibits arginine-induced insulin secretion in MIN6 cells

Diabetologia ◽  
1999 ◽  
Vol 42 (7) ◽  
pp. 887-891 ◽  
Author(s):  
Y. Tanizawa ◽  
Y. Ohta ◽  
J. Nomiyama ◽  
K. Matsuda ◽  
K. Tanabe ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Min6 Cells ◽  
Negative Mutant

Dominant-negative mutant hepatocyte nuclear factor 1α induces diabetes in transgenic-cloned pigs

2009 ◽  
Vol 18 (5) ◽  
pp. 697-706 ◽  
Author(s):  
Kazuhiro Umeyama ◽  
Masahito Watanabe ◽  
Hitoshi Saito ◽  
Mayuko Kurome ◽  
Sadaaki Tohi ◽  
...  
Keyword(s):  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 1Α ◽  
Negative Mutant

scholarly journals Zyxin regulates migration of renal epithelial cells through activation of hepatocyte nuclear factor-1β

2013 ◽  
Vol 305 (1) ◽  
pp. F100-F110 ◽  
Author(s):  
Yun-Hee Choi ◽  
Brian T. McNally ◽  
Peter Igarashi
Keyword(s):  
Transcription Factor ◽  
Epithelial Cells ◽  
Nuclear Translocation ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Epithelial Tissue ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Lim Domain ◽  
Renal Epithelial Cells

Hepatocyte nuclear factor-1β (HNF-1β) is an epithelial tissue-specific transcription factor that regulates gene expression in the kidney, liver, pancreas, intestine, and other organs. Mutations of HNF-1β in humans produce renal cysts and congenital kidney anomalies. Here, we identify the LIM-domain protein zyxin as a novel binding partner of HNF-1β in renal epithelial cells. Zyxin shuttles to the nucleus where it colocalizes with HNF-1β. Immunoprecipitation of zyxin in leptomycin B-treated cells results in coprecipitation of HNF-1β. The protein interaction requires the second LIM domain of zyxin and two distinct domains of HNF-1β. Overexpression of zyxin stimulates the transcriptional activity of HNF-1β, whereas small interfering RNA silencing of zyxin inhibits HNF-1β-dependent transcription. Epidermal growth factor (EGF) induces translocation of zyxin into the nucleus and stimulates HNF-1β-dependent promoter activity. The EGF-mediated nuclear translocation of zyxin requires activation of Akt. Expression of dominant-negative mutant HNF-1β, knockdown of zyxin, or inhibition of Akt inhibits EGF-stimulated cell migration. These findings reveal a novel pathway by which extracellular signals are transmitted to the nucleus to regulate the activity of a transcription factor that is essential for renal epithelial differentiation.

scholarly journals Conditional expression of hepatocyte nuclear factor-1β, the maturity-onset diabetes of the young-5 gene product, influences the viability and functional competence of pancreatic β-cells

2006 ◽  
Vol 190 (1) ◽  
pp. 171-181 ◽  
Author(s):  
Hannah J Welters ◽  
Sabine Senkel ◽  
Ludger Klein-Hitpass ◽  
Silke Erdmann ◽  
Heike Thomas ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Insulin Secretion ◽  
Dominant Negative ◽  
Nuclear Factor ◽  
Maturity Onset Diabetes ◽  
Hepatocyte Nuclear Factor ◽  
Β Cells ◽  
Β Cell ◽  
Onset Diabetes ◽  
Conditional Expression

Mutations in the gene encoding hepatocyte nuclear factor (HNF)1β result in maturity-onset diabetes of the young-(MODY)5, by impairing insulin secretory responses and, possibly, by reducing β-cell mass. The functional role of HNF1β in normal β-cells is poorly understood; therefore, in the present study, wild-type (WT) HNF1β, or one of two naturally occurring MODY5 mutations (an activating mutation, P328L329del, or a dominant-negative form, A263insGG) were conditionally expressed in the pancreatic β-cell line, insulin-1 (INS-1), and the functional consequences examined. Surprisingly, overexpression of the dominant-negative mutant did not modify any of the functional properties of the cells studied (including insulin secretion, cell growth and viability). By contrast, expression of WT HNF1β was associated with a time- and dose-dependent inhibition of INS-1 cell proliferation and a marked increase in apoptosis. Induction of WT HNF1β also inhibited the insulin secretory response to nutrient stimuli, membrane depolarisation or activation of protein kinases A and C and this correlated with a significant decrease in pancrease-duodenum homeobox-1 protein levels. The attenuation of insulin secretion was, however, dissociated from the inhibition of proliferation and loss of viability, since expression of the P328L329del mutant led to a reduced rate of cell proliferation, but failed to induce apoptosis or to alter insulin secretion. Taken together, the present results suggest that mature rodent β-cells are sensitive to increased expression of WT HNF1β and they imply that the levels of this protein are tightly regulated to maintain secretory competence and cell viability.

Regulation of kidney-specific Ksp-cadherin gene promoter by hepatocyte nuclear factor-1β

2002 ◽  
Vol 283 (4) ◽  
pp. F839-F851 ◽  
Author(s):  
Yun Bai ◽  
Marco Pontoglio ◽  
Thomas Hiesberger ◽  
Angus M. Sinclair ◽  
Peter Igarashi
Keyword(s):  
Promoter Activity ◽  
Gene Promoter ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Specific Gene ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Tissue Specific ◽  
Transfected Cells

Kidney-specific cadherin (Ksp-cadherin) is a tissue-specific member of the cadherin family that is expressed exclusively in the kidney and developing genitourinary tract. Recent studies have shown that the proximal 250 bp of the Ksp-cadherin gene promoter are sufficient to direct tissue-specific gene expression in vivo and in vitro. The proximal 120 bp of the promoter are evolutionarily conserved between mouse and human and contain a DNase I hypersensitive site that is kidney cell specific. At position −55, the promoter contains a consensus recognition site for hepatocyte nuclear factor-1 (HNF-1). Mutations of the consensus HNF-1 site and downstream GC-boxes inhibit promoter activity in transfected cells. HNF-1α and HNF-1β bind specifically to the −55 site, and both proteins transactivate the promoter directly. Expression of Ksp-cadherin is not altered in the kidneys of HNF-1α-deficient mice. However, expression of a gain-of-function HNF-1β mutant stimulates Ksp-cadherin promoter activity in transfected cells, whereas expression of a dominant-negative mutant inhibits activity. These studies identify Ksp-cadherin as the first kidney-specific promoter that has been shown to be regulated by HNF-1β. Mutations of HNF-1β, as occur in humans with inherited renal cysts and diabetes, may cause dysregulated Ksp-cadherin promoter activity.

Mutation P291fsinsC in the transcription factor hepatocyte nuclear factor-1alpha is dominant negative

Diabetes ◽  
1998 ◽  
Vol 47 (8) ◽  
pp. 1231-1235 ◽  
Author(s):  
K. Yamagata ◽  
Q. Yang ◽  
K. Yamamoto ◽  
H. Iwahashi ◽  
J. Miyagawa ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Dominant Negative ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor
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