c-Myc controls proliferation versus differentiation in human pancreatic endocrine cells.
Using immortalized human pancreatic endocrine cell lines, we have shown previously that differentiation into hormone-expressing cells requires cell-cell contact acting in synergy with the homeodomain transcription factor pancreatic duodenal homeobox-1 (PDX-1). Although differentiation is associated with a decrease in cell proliferation, the mechanisms behind this relationship are not known. Using TRM-6, a delta cell line, and betalox5, a beta-cell line, we show here that cell-cell contact and subsequent endocrine differentiation lead to a down-regulation of the c-myc protooncogene. Overexpression of c-Myc obtained with an inducible c-Myc-estrogen receptor fusion protein results in an increase in cell proliferation and the ablation of hormone expression. Moreover, we show that although c-Myc is expressed in a subset of cells from the human fetal and adult pancreas, it is absent in differentiated endocrine cells. The mechanism by which c-Myc interferes with hormone expression may be through effects on the homeodomain transcription factor PDX-1, as immunostaining for PDX-1 in cells with activated c-Myc revealed a redistribution of PDX-1 from the nucleus to the cytoplasm. These results suggest that c-Myc plays a central role in a cell-cell contact-mediated switch mechanism by which cell division vs. differentiation in endocrine cells is determined.
Demeterco
Carla
C
Cancer Center, University of California-San Diego, 1st Floor Building 7, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Itkin-Ansari
Pamela
P
Tyrberg
Björn
B
Ford
Lance P
LP
Jarvis
Richard A
RA
Levine
Fred
F
D000328:Adult; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D005333:Fetus / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006367:HeLa Cells; D018398:Homeodomain Proteins; D006801:Humans; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D010187:Pancreatic Hormones / Q000037:antagonists & inhibitors; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014178:Translocation, Genetic
D018398:Homeodomain Proteins; D007328:Insulin; D010187:Pancreatic Hormones; D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein