Diminished Pancreatic β-Cell Mass in Securin-Null Mice Is Caused by β-Cell Apoptosis and Senescence
Copyright policy )Diminished Pancreatic β-Cell Mass in Securin-Null Mice Is Caused by β-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.
- University of California, Los Angeles United States
- University of California System United States
- University of California, San Francisco United States
- CEDARS-SINAI MEDICAL CENTER
- Cedars-Sinai Medical Center United States
Cyclin-Dependent Kinase Inhibitor p21, Male, Apoptosis, Mice, Transgenic, beta-Galactosidase, Securin, Mice, Insulin-Secreting Cells, Animals, Female, Carrier Proteins, Cellular Senescence, Gene Deletion, Cell Proliferation, DNA Damage
Cyclin-Dependent Kinase Inhibitor p21, Male, Apoptosis, Mice, Transgenic, beta-Galactosidase, Securin, Mice, Insulin-Secreting Cells, Animals, Female, Carrier Proteins, Cellular Senescence, Gene Deletion, Cell Proliferation, DNA Damage
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