HES6 reverses nuclear reprogramming of insulin-producing cells following cell fusion.
To examine the mechanism by which growth-stimulated pancreatic beta-cells dedifferentiate, somatic cell fusions were performed between MIN6, a highly differentiated mouse insulinoma, and betalox5, a cell line derived from human beta-cells which progressively dedifferentiated in culture. MIN6/betalox5 somatic cells hybrids underwent silencing of insulin expression and a marked decline in PDX1, NeuroD, and MafA, indicating that betalox5 expresses a dominant transacting factor(s) that represses beta-cell differentiation. Expression of Hes1, which inhibits endocrine differentiation was higher in hybrid cells than in parental MIN6 cells. Hes6, a repressor of Hes1, was highly expressed in primary beta-cells as well as MIN6, but was repressed in hybrids. Hes6 overexpression using a retroviral vector led to a decrease in Hes1 levels, an increase in beta-cell transcription factors and partial restoration of insulin expression. We conclude that the balance of Notch activators and inhibitors may play an important role in maintaining the beta-cell differentiated state.
Ball
Andrew J
AJ
UCSD Department of Pediatrics, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0816, USA.
Abrahamsson
Annelie E
AE
Tyrberg
Björn
B
Itkin-Ansari
Pamela
P
Levine
Fred
F
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002459:Cell Fusion; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D006822:Hybrid Cells; D007328:Insulin / Q000096:biosynthesis*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D016133:Polymerase Chain Reaction; D012097:Repressor Proteins / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D012097:Repressor Proteins; D015534:Trans-Activators; C411859:HES6 protein, human; C084010:pancreatic and duodenal homeobox 1 protein