The Human Glucokinase Gene β-Cell-Type Promoter: An Essential Role of Insulin Promoter Factor 1/PDX-1 in Its Activation in HIT-T15 Cells

Watada, Hirotaka; Kajimoto, Yoshitaka; Umayahara, Yutaka; Matsuoka, Taka‐aki; Kaneto, Hideaki; Fujitani, Yoshi; Kamada, Takenobu; Kawamori, Ryuzo; Yamasaki, Yoshimitsu

doi:10.2337/diab.45.11.1478

Cited by 184 publications

(100 citation statements)

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“…Watada et al (52) demonstrated that the promoter region of the human GK gene comprises multiple cis-acting elements, including two very important cis-motifs: the palindrome structure hPal-1, and the insulin gene cis-motif-A-element-like hUPE3. PDX-1 binds the hUPE3 motif to activate the transcription of GK.…”

Section: Gkmentioning

confidence: 99%

Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood

Hui

Perfetti²

2002

European Journal of Endocrinology

121

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Pancreas duodenum homeobox-1 (PDX-1) (also known as insulin promoter factor-1, islet/duodenum homeobox-1, somatostatin transactivating factor-1, insulin upstream factor-1 and glucose-sensitive factor) is a transcription factor encoded by a Hox-like homeodomain gene. In humans and other animal species, the embryonic development of the pancreas requires PDX-1, as demonstrated by the identification of an individual with pancreatic agenesis resulting from a mutation that impaired the transcription of a functionally active PDX-1 protein. In adult subjects, PDX-1 is essential for normal pancreatic islet function as suggested by its regulatory action on the expression of a number of pancreatic genes, including insulin, somatostatin, islet amyloid polypeptide, the glucose transporter type 2 and glucokinase. Furthermore, heterozygous mutations of PDX-1 have been linked to a type of autosomal dominant form of diabetes mellitus known as maturity onset diabetes of the young type 4. The dual action of PDX-1, as a differentiation factor during embryogenesis and as a regulator of islet cell physiology in mature islet cells, underscores the unique role of PDX-1 in health and disease of the human endocrine pancreas.

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Section: Gkmentioning

confidence: 99%

Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood

Hui

Perfetti²

2002

European Journal of Endocrinology

121

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“…One of the second pair of mirror sections was used to stain either glucagon or somatostatin plus insulin, whereas insulin promoter factor 1/PDX-1 (IPF1/PDX-1) and DCK were double immunostained in the other section (1,18). The sections were immunostained for glucagon or somatostatin by incubation with a polyclonal rabbit anti-glucagon antibody (Linco Research) or a polyclonal rabbit anti-somatostatin antibody (Dako), respectively.…”

Section: Staining Of Isletsmentioning

confidence: 99%

Recombinant human betacellulin promotes the neogenesis of beta-cells and ameliorates glucose intolerance in mice with diabetes induced by selective alloxan perfusion.

et al. 2000

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Betacellulin (BTC), a member of the epidermal growth factor family, is expressed predominantly in the human pancreas and induces the differentiation of a pancreatic acinar cell line (AR42J) into insulin-secreting cells, suggesting that BTC has a physiologically important role in the endocrine pancreas. In this study, we examined the in vivo effect of recombinant human BTC (rhBTC) on glucose intolerance and pancreatic morphology using a new mouse model with glucose intolerance induced by selective alloxan perfusion. RhBTC (1 µg/g body wt) or saline was injected subcutaneously every day from the day after alloxan treatment. The intraperitoneal glucose tolerance test revealed no difference between rhBTC-treated and rhBTC-untreated glucose-intolerant mice at 2-4 weeks. However, glucose tolerance was significantly improved and body weight was significantly increased in rhBTC-treated mice compared with untreated mice at 8 weeks. Islet-like cell clusters, consisting mainly of ␤-cells, were increased in the pancreas and were localized in contact with the ductal lining cells and sometimes with acinar cells. In conclusion, administration of rhBTC improved glucose tolerance in this mouse model by increasing ␤-cell volume, primarily through accelerated neogenesis from ductal lining cells.

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“…PDX-1 can specifically stimulate reporter gene expression from transfected constructs driven by promoter sequences from several genes that are normally transcribed selectively in ␤ cells, including insulin (7)(8)(9)(10)(11), glucokinase (12), islet amyloid polypeptide (13)(14)(15)(16), and glucose transporter type 2 (GLUT2) 1 (17). The importance of PDX-1 in controlling the expression of genes required for the sensing and regulation of blood glucose levels suggested that an inactivating mutation within the protein would result in dysfunctional ␤ cells.…”

mentioning

confidence: 99%

Pancreatic β Cell-specific Transcription of thepdx-1 Gene

Gerrish¹,

Gannon²,

Shih³

et al. 2000

Journal of Biological Chemistry

146

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To identify potential transactivators of pdx-1, we sequenced approximately 4.5 kilobases of the 5 promoter region of the human and chicken homologs, assuming that sequences conserved with the mouse gene would contain critical cis-regulatory elements. The sequences associated with hypersensitive site 1 (HSS1) represented the principal area of homology within which three conserved subdomains were apparent: area I (؊2694 to ؊2561 base pairs (bp)), area II (؊2139 to ؊1958 bp), and area III (؊1879 to ؊1799 bp). The identities between the mouse and chicken/human genes are very high, ranging from 78 to 89%, although only areas I and III are present within this region in chicken. Pancreatic ␤ cell-selective expression was shown to be controlled by mouse and human area I or area II, but not area III, from an analysis of pdx-1-driven reporter activity in transfected ␤-and non-␤ cells. Mutational and functional analyses of conserved hepatic nuclear factor 3 (HNF3)-like sites located within area I and area II demonstrated that activation by these regions was mediated by HNF3␤. To determine if a similar regulatory relationship might exist within the context of the endogenous gene, pdx-1 expression was measured in embryonic stem cells in which one or both alleles of HNF3␤ were inactivated. pdx-1 mRNA levels induced upon differentiation to embryoid bodies were down-regulated in homozygous null HNF3␤ cells. Together, these results suggest that the conserved sequences represented by areas I and II define the binding sites for factors such as HNF3␤, which control islet ␤ cell-selective expression of the pdx-1 gene.The PDX-1 homeodomain transcription factor is an essential regulator of pancreatic endocrine cell development and adult islet ␤ cell function. Pancreatic development in homozygous pdx-1 Ϫ/Ϫ mice is blocked at a very early stage (1-3), and endocrine cells in the rostral duodenum (3) and stomach (4) are also reduced or absent. The finding that a human born without a pancreas was homozygous for an inactivating mutation in pdx-1 (5) highlights the critical conserved role that this factor plays in pancreas formation in vertebrates.In the adult pancreas, PDX-1 is expressed at highest levels within islet ␤ cells (6). PDX-1 can specifically stimulate reporter gene expression from transfected constructs driven by promoter sequences from several genes that are normally transcribed selectively in ␤ cells, including insulin (7-11), glucokinase (12), islet amyloid polypeptide (13-16), and glucose transporter type 2 (GLUT2) 1 (17). The importance of PDX-1 in controlling the expression of genes required for the sensing and regulation of blood glucose levels suggested that an inactivating mutation within the protein would result in dysfunctional ␤ cells. Indeed, mice that are heterozygous mutant carriers of PDX-1 exhibit symptoms of glucose intolerance, suggesting a dosage effect on insulin expression and ␤ cell function (18,19). More significantly, humans with this condition are susceptible to a form of Type II (non-insulin-dependent)...

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The Human Glucokinase Gene β-Cell-Type Promoter: An Essential Role of Insulin Promoter Factor 1/PDX-1 in Its Activation in HIT-T15 Cells

Cited by 184 publications

References 0 publications

Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood

Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood

Recombinant human betacellulin promotes the neogenesis of beta-cells and ameliorates glucose intolerance in mice with diabetes induced by selective alloxan perfusion.

Pancreatic β Cell-specific Transcription of thepdx-1 Gene

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