Abstract
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.
Highlights
Pancreatic and duodenal homeobox-1 (PDX-1) is a homeodomain-containing transcription factor and plays an essential role in a variety of cellular processes, including pancreatic development, β-cell differentiation, maintenance of normal β-cell function and tumorigenesis
To confirm the positive regulation of pancreatic and duodenal homeobox-1 (PDX-1) expression by Notch1 activation, we examined the effect of Notch1 intracellular domain (NICD)
Our studies show that NICD-enhanced PDX-1 expression was accompanied by increased insulin expression/secretion and cell proliferation in β cells of transgenic βNICD+/+ mice, resulting in hyperinsulinemia and hypoglycemia, as well as an altered response to Intraperitoneal Glucose Tolerance Test (IPGTT) in these mice
Summary
Pancreatic and duodenal homeobox-1 (PDX-1) is a homeodomain-containing transcription factor and plays an essential role in a variety of cellular processes, including pancreatic development, β-cell differentiation, maintenance of normal β-cell function and tumorigenesis. Targeted ablation of pdx-1 gene in mice [1] and a homozygous nonsense mutation in the human pdx-1 gene [2] results in pancreatic agenesis. Mice with β-cell-specific ablation of pdx-1 develop overt diabetes [3], whereas heterozygosity for the null mutation of pdx-1 results in decreased insulin expression/secretion [3,4] and predispose islets to apoptosis [5]. Gene mutations in human pdx-1 lead to the development of diabetes [6]. The involvement of PDX-1 in tumorigenesis is evidenced by its overexpression in a variety of human cancers including pancreatic neuroendocrine tumor (PNET) [7,8,9,10,11,12,13] and by the significant correlation of PDX-1 overexpression with the pathological parameters of cancer patients (e.g., metastasis and histological grade) [9,14]. Recent studies have demonstrated the oncogenic properties of PDX-1 as it stimulates cell proliferation, colony formation, invasion and tumor growth [15] and is required for K-RasG12D to induce the development of
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