Notch1 Activation Up-Regulates Pancreatic and Duodenal Homeobox-1
Transcription factor pancreatic and duodenal homeobox-1 (PDX-1) plays an essential role in pancreatic development, β-cell differentiation, maintenance of normal β-cell function and tumorigenesis. PDX-1 expression is tightly controlled through a variety of mechanisms under different cellular contexts...
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doaj-a120faf0fd694ce8af99303a28acebf22020-11-25T00:21:06ZengMDPI AGGenes2073-44252013-07-014335837410.3390/genes4030358Notch1 Activation Up-Regulates Pancreatic and Duodenal Homeobox-1Min LiF. Charles BrunicardiWilliam E. FisherDavid DawsonNeil SenzerJames WuJohn NemunaitisShi-He LiuGuisheng ZhouJuehua YuTranscription factor pancreatic and duodenal homeobox-1 (PDX-1) plays an essential role in pancreatic development, β-cell differentiation, maintenance of normal β-cell function and tumorigenesis. PDX-1 expression is tightly controlled through a variety of mechanisms under different cellular contexts. We report here that overexpression of Notch1 intracellular domain (NICD), an activated form of Notch1, enhanced PDX-1 expression in both PDX-1 stable HEK293 cells and mouse insulinoma β-TC-6 cells, while NICD shRNA inhibited the enhancing effect. NICD-enhanced PDX-1 expression was accompanied by increased insulin expression/secretion and cell proliferation in β-TC-6 cells, which was reversed by NICD shRNA. Cre activation-induced specific expression of NICD in islet β cells of transgenic βNICD+/+ mice induced increased expression of PDX-1, insulin and proliferating cell nuclear antigen (PCNA) and decreased expression of p27 with accompanied fasting hyperinsulinemia and hypoglycemia and altered responses to intraperitoneal glucose tolerance test. Systemically delivered NICD shRNA suppressed islet expression of PDX-1 and reversed the hypoglycemia and hyperinsulinemia. Moreover, expression levels of NICD were correlated with those of PDX-1 in human pancreatic neuroendocrine tumor. Thus, Notch1 acts as a positive regulator for PDX-1 expression, cooperates with PDX-1 in the development of insulin overexpression and islet cell neoplasia and represents a potential therapeutic target for islet neoplasia.http://www.mdpi.com/2073-4425/4/3/358Notch1NICDPDX-1insulinhyperinsulinemiahypoglycemia |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Min Li F. Charles Brunicardi William E. Fisher David Dawson Neil Senzer James Wu John Nemunaitis Shi-He Liu Guisheng Zhou Juehua Yu |
spellingShingle |
Min Li F. Charles Brunicardi William E. Fisher David Dawson Neil Senzer James Wu John Nemunaitis Shi-He Liu Guisheng Zhou Juehua Yu Notch1 Activation Up-Regulates Pancreatic and Duodenal Homeobox-1 Genes Notch1 NICD PDX-1 insulin hyperinsulinemia hypoglycemia |
author_facet |
Min Li F. Charles Brunicardi William E. Fisher David Dawson Neil Senzer James Wu John Nemunaitis Shi-He Liu Guisheng Zhou Juehua Yu |
author_sort |
Min Li |
title |
Notch1 Activation Up-Regulates Pancreatic and Duodenal Homeobox-1 |
title_short |
Notch1 Activation Up-Regulates Pancreatic and Duodenal Homeobox-1 |
title_full |
Notch1 Activation Up-Regulates Pancreatic and Duodenal Homeobox-1 |
title_fullStr |
Notch1 Activation Up-Regulates Pancreatic and Duodenal Homeobox-1 |
title_full_unstemmed |
Notch1 Activation Up-Regulates Pancreatic and Duodenal Homeobox-1 |
title_sort |
notch1 activation up-regulates pancreatic and duodenal homeobox-1 |
publisher |
MDPI AG |
series |
Genes |
issn |
2073-4425 |
publishDate |
2013-07-01 |
description |
Transcription factor pancreatic and duodenal homeobox-1 (PDX-1) plays an essential role in pancreatic development, β-cell differentiation, maintenance of normal β-cell function and tumorigenesis. PDX-1 expression is tightly controlled through a variety of mechanisms under different cellular contexts. We report here that overexpression of Notch1 intracellular domain (NICD), an activated form of Notch1, enhanced PDX-1 expression in both PDX-1 stable HEK293 cells and mouse insulinoma β-TC-6 cells, while NICD shRNA inhibited the enhancing effect. NICD-enhanced PDX-1 expression was accompanied by increased insulin expression/secretion and cell proliferation in β-TC-6 cells, which was reversed by NICD shRNA. Cre activation-induced specific expression of NICD in islet β cells of transgenic βNICD+/+ mice induced increased expression of PDX-1, insulin and proliferating cell nuclear antigen (PCNA) and decreased expression of p27 with accompanied fasting hyperinsulinemia and hypoglycemia and altered responses to intraperitoneal glucose tolerance test. Systemically delivered NICD shRNA suppressed islet expression of PDX-1 and reversed the hypoglycemia and hyperinsulinemia. Moreover, expression levels of NICD were correlated with those of PDX-1 in human pancreatic neuroendocrine tumor. Thus, Notch1 acts as a positive regulator for PDX-1 expression, cooperates with PDX-1 in the development of insulin overexpression and islet cell neoplasia and represents a potential therapeutic target for islet neoplasia. |
topic |
Notch1 NICD PDX-1 insulin hyperinsulinemia hypoglycemia |
url |
http://www.mdpi.com/2073-4425/4/3/358 |
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