Pituitary tumor transforming gene-null male mice exhibit impaired pancreatic beta cell proliferation and diabetes.
The mammalian securin, pituitary tumor transforming gene (PTTG), regulates sister chromatid separation during mitosis. Mice or cell lines deficient in PTTG expression, however, are surprisingly viable. Here we show that PTTG disruption in mice (PTTG-/-) severely impairs glucose homeostasis leading to diabetes during late adulthood, especially in males associated with nonautoimmune insulinopenia and reversed alphabeta cell ratio. Islet beta cell mass in PTTG-/- mice was already diminished before development of frank diabetes and only increased minimally during growth. BrdUrd incorporation of islet cells in PTTG-null mice was approximately 65% lower (P < 0.005) than in the WT pancreas, whereas apoptosis rates were similar. PTTG-/- beta cells had pleiotropic nuclei, suggesting defects in cell division. The results indicated that securin is indispensable for normal pancreatic beta cell proliferation.
Wang
Zhiyong
Z
Department of Medicine, Cedars-Sinai Research Institute, University of California School of Medicine, Los Angeles, CA 90048, USA.
Moro
Enrico
E
Kovacs
Kalman
K
Yu
Run
R
Melmed
Shlomo
S
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D002455:Cell Division; D002467:Cell Nucleus / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D006943:Hyperglycemia / Q000209:etiology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000473:pathology*; D008060:Lipodystrophy / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D064249:Securin
D007328:Insulin; D009363:Neoplasm Proteins; D064249:Securin; D001973:Bromodeoxyuridine