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. 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.
Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA. sliu@mednet.ucla.edu.
Shi-He
SH
Liu
Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA. ddawson@mednet.ucla.edu.
Guisheng
G
Zhou
Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA. juehuayu@mednet.ucla.edu.
Juehua
J
Yu
Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA. jameswu@mednet.ucla.edu.
James
J
Wu
Mary Crowley Cancer Research Center, Dallas, TX 75230, USA. jnemunaitis@marycrowley.org.
John
J
Nemunaitis
Mary Crowley Cancer Research Center, Dallas, TX 75230, USA. nsenzer@marycrowley.org.
Neil
N
Senzer
CURE: Digestive Disease Research Center, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA. ddawson@mednet.ucla.edu.
David
D
Dawson
Department of Neurosurgery, UT-Houston School of Medicine, Houston, TX 77030, USA. min.li@uth.tmc.edu.
Min
M
Li
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA. wfisher@bcm.edu.
William E
WE
Fisher
Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA. cbrunicardi@mednet.ucla.edu.
F Charles
FC
Brunicardi