共查询到20条相似文献,搜索用时 421 毫秒
1.
Human insulin gene is a target gene of hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-1beta. 总被引:6,自引:0,他引:6
K Okita Q Yang K Yamagata K A Hangenfeldt J Miyagawa Y Kajimoto H Nakajima M Namba C B Wollheim T Hanafusa Y Matsuzawa 《Biochemical and biophysical research communications》1999,263(2):566-569
2.
3.
4.
Laine B Eeckhoute J Suaud L Briche I Furuta H Bell GI Formstecher P 《FEBS letters》2000,479(1-2):41-45
Mutations in the hepatocyte nuclear factor 4alpha (HNF-4alpha) gene are associated with one form of maturity-onset diabetes of the young (MODY1). The R154X mutation generates a protein lacking the E-domain which is required for normal HNF-4alpha functions. Since pancreatic beta-cell dysfunction is a feature of MODY1 patients, we compared the functional properties of the R154X mutant in insulin-secreting pancreatic beta-cells and non-beta-cells. The R154X mutation did not affect nuclear localisation in beta-cells and non-beta-cells. However, it did lead to a greater impairment of HNF-4a function in beta-cells compared to non-beta-cells, including a complete loss of transactivation activity and a dominant-negative behaviour. . 相似文献
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Gu N Adachi T Matsunaga T Takeda J Tsujimoto G Ishihara A Yasuda K Tsuda K 《Biochemical and biophysical research communications》2006,346(3):1016-1023
Dipeptidylpeptidase IV (DPP-IV) is a well-documented drug target for the treatment of type 2 diabetes. Hepatocyte nuclear factors (HNF)-1alpha and HNF-1beta, known as the causal genes of MODY3 and MODY5, respectively, have been reported to be involved in regulation of DPP-IV gene expression. But, it is not completely clear (i) that they play roles in regulation of DPP-IV gene expression, and (ii) whether DPP-IV gene activity is changed by mutant HNF-1alpha and mutant HNF-1beta in MODY3 and MODY5. To explore these questions, we investigated transactivation effects of wild HNF-1alpha and 13 mutant HNF-1alpha, as well as wild HNF-1beta and 2 mutant HNF-1beta, on DPP-IV promoter luciferase gene in Caco-2 cells by means of a transient experiment. Both wild HNF-1alpha and wild HNF-1beta significantly transactivated DPP-IV promoter, but mutant HNF-1alpha and mutant HNF-1beta exhibited low transactivation activity. Moreover, to study whether mutant HNF-1alpha and mutant HNF-1beta change endogenous DPP-IV enzyme activity, we produced four stable cell lines from Caco-2 cells, in which wild HNF-1alpha or wild HNF-1beta, or else respective dominant-negative mutant HNF-1alphaT539fsdelC or dominant-negative mutant HNF-1betaR177X, was stably expressed. We found that DPP-IV gene expression and enzyme activity were significantly increased in wild HNF-1alpha cells and wild HNF-1beta cells, whereas they decreased in HNF-1alphaT539fsdelC cells and HNF-1betaR177X cells, compared with DPP-IV gene expression and enzyme activity in Caco-2 cells. These results suggest that both wild HNF-1alpha and wild HNF-1beta have a stimulatory effect on DPP-IV gene expression, but that mutant HNF-1alpha and mutant HNF-1beta attenuate the stimulatory effect. 相似文献
16.
Timothy M. Frayling Michael P. Bulman Maggie Appleton A. T. Hattersley Sian Ellard 《Human genetics》1997,101(3):351-354
Non-insulin dependent diabetes (NIDDM) is a polygenic heterogeneous disorder of glucose homeostasis. Maturity-onset diabetes
of the young (MODY) is a monogenic subtype of NIDDM characterised by early-onset (< 25 years) and autosomal dominant inheritance.
Mutations in the hepatocyte nuclear factor 1 alpha (HNF-1α) gene have recently been shown to cause MODY. The incidence of
mutations in this gene in MODY and late-onset NIDDM is not known. We have developed a rapid specific polymerase chain reaction
test for HNF-1α mutations; this test involves the use of fluorescently labelled forward primers and modified reverse primers
to detect length polymorphisms resulting from frameshift mutations. With this method, we have screened 102 MODY probands,
viz. 60 defined according to strict diagnostic criteria (autosomal dominant inheritance and at least one member diagnosed
age < 25 years) and 95 late-onset NIDDM probands (diagnosed 35–70 years with ≥ 1 affected relative), for the presence of 9
known HNF-1α frameshift mutations, including 6 that occur at two sites for recurring mutation (residues 291/292 and 379).
Mutations were detected in 11 of the strictly defined MODY probands and one mutation was also found in a single subject with
early-onset NIDDM but no family history of the disease. The HNF-1α frameshift mutations were not detected in any late-onset
NIDDM subjects, suggesting these mutations do not have a major role in the pathogenesis of NIDDM. Our results indicate that
the prevalence of the nine frameshift mutations in strictly defined UK MODY is 18%, with the P291fsinsC mutation alone having
a frequency of 13%.
Received: 13 May 1997 / Accepted: 13 August 1997 相似文献
17.
18.
19.
20.