Diminished pancreatic beta-cell mass in securin-null mice is caused by beta-cell apoptosis and senescence.

Abstract

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.

• Authors: Vera Chesnokova, Chris Wong, Svetlana Zonis, Anna Gruszka, Kolja Wawrowsky, Song-Guang Ren, Anat Benshlomo, Run Yu
• Journal: Endocrinology (Endocrinology) Vol. 150 Issue 6 Pg. 2603-10 (Jun 2009) ISSN: 1945-7170 [Electronic] United States
• PMID: 19213844 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Carrier Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• Securin
• beta-Galactosidase

Topics

• Animals
• Apoptosis (physiology)
• Carrier Proteins (genetics, metabolism)
• Cell Proliferation
• Cellular Senescence (physiology)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• DNA Damage (physiology)
• Female
• Gene Deletion
• Insulin-Secreting Cells (metabolism, pathology)
• Male
• Mice
• Mice, Transgenic
• Securin
• beta-Galactosidase (metabolism)