Diminished pancreatic beta-cell mass in securin-null mice is caused by beta-cell apoptosis and senescence.
Pituitary tumor transforming gene (PTTG) encodes a securin protein critical in regulating chromosome separation. PTTG-null (PTTG(-/-)) mice exhibit pancreatic beta-cell hypoplasia and insulinopenic diabetes. We tested whether PTTG deletion causes beta-cell senescence, resulting in diminished beta-cell mass. We examined beta-cell mass, proliferation, apoptosis, neogenesis, cell size, and senescence in PTTG(-/-) and WT mice from embryo to young adulthood before diabetes is evident. The roles of cyclin-dependent kinase inhibitors and DNA damage in the pathogenesis of diabetes in PTTG(-/-) mice were also addressed. Relative beta-cell mass in PTTG(-/-) mice began to decrease at 2-3 wk, whereas beta-cell proliferation rate was initially normal but decreased in PTTG(-/-) mice beginning at 2 months. Apoptosis was also much more evident in PTTG(-/-) mice. At 1 month, beta-cell neogenesis was robust in wild-type mice but was absent in PTTG(-/-) mice. In addition, the size of beta-cells became larger and macronuclei were prominent in PTTG(-/-) animals. Senescence-associated beta-galactosidase was also active in PTTG(-/-) beta-cells at 1 month. Cyclin-dependent kinase inhibitor p21 was progressively up-regulated in PTTG(-/-) islets, and p21 deletion partially rescued PTTG(-/-) mice from development of diabetes. mRNA array showed that DNA damage-associated genes were activated in PTTG(-/-) islets. We conclude that beta-cell apoptosis and senescence contribute to the diminished beta-cell mass in PTTG(-/-) mice, likely secondary to DNA damage. Our results also suggest that ductal progenitor beta-cells are exhausted by excessive neogenesis induced by apoptosis in PTTG(-/-) mice.
Chesnokova
Vera
V
Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90048, USA.
Wong
Chris
C
Zonis
Svetlana
S
Gruszka
Anna
A
Wawrowsky
Kolja
K
Ren
Song-Guang
SG
Benshlomo
Anat
A
Yu
Run
R
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D005260:Female; D017353:Gene Deletion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D064249:Securin; D001616:beta-Galactosidase / Q000378:metabolism
D002352:Carrier Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D064249:Securin; D001616:beta-Galactosidase