Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice.
E2F transcription factors are thought to be key regulators of cell growth control. Here we use mutant mouse strains to investigate the function of E2F1 and E2F2 in vivo. E2F1/E2F2 compound-mutant mice develop nonautoimmune insulin-deficient diabetes and exocrine pancreatic dysfunction characterized by endocrine and exocrine cell dysplasia, a reduction in the number and size of acini and islets, and their replacement by ductal structures and adipose tissue. Mutant pancreatic cells exhibit increased rates of DNA replication but also of apoptosis, resulting in severe pancreatic atrophy. The expression of genes involved in DNA replication and cell cycle control was upregulated in the E2F1/E2F2 compound-mutant pancreas, suggesting that their expression is repressed by E2F1/E2F2 activities and that the inappropriate cell cycle found in the mutant pancreas is likely the result of the deregulated expression of these genes. Interestingly, the expression of ductal cell and adipocyte differentiation marker genes was also upregulated, whereas expression of pancreatic cell marker genes were downregulated. These results suggest that E2F1/E2F2 activity negatively controls growth of mature pancreatic cells and is necessary for the maintenance of differentiated pancreatic phenotypes in the adult.
Iglesias
Ainhoa
A
Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Sciences, University of the Basque Country, Bilbao, Spain.
Murga
Matilde
M
Laresgoiti
Usua
U
Skoudy
Anouchka
A
Bernales
Irantzu
I
Fullaondo
Asier
A
Moreno
Bernardino
B
Lloreta
José
J
Field
Seth J
SJ
Real
Francisco X
FX
Zubiaga
Ana M
AM
D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002455:Cell Division; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D010188:Exocrine Pancreatic Insufficiency / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D007515:Islets of Langerhans / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D010179:Pancreas / Q000473:pathology; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; C493754:E2f1 protein, mouse; C484940:E2f2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors