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Articles by A BenShlomo
Total Records ( 1 ) for A BenShlomo
  V Chesnokova , C Wong , S Zonis , A Gruszka , K Wawrowsky , S. G Ren , A BenShlomo and R. Yu
 

Pituitary tumor transforming gene (PTTG) encodes a securin protein critical in regulating chromosome separation. PTTG-null (PTTG–/–) mice exhibit pancreatic β-cell hypoplasia and insulinopenic diabetes. We tested whether PTTG deletion causes β-cell senescence, resulting in diminished β-cell mass. We examined β-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 β-cell mass in PTTG–/– mice began to decrease at 2–3 wk, whereas β-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, β-cell neogenesis was robust in wild-type mice but was absent in PTTG–/– mice. In addition, the size of β-cells became larger and macronuclei were prominent in PTTG–/– animals. Senescence-associated β-galactosidase was also active in PTTG–/– β-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 β-cell apoptosis and senescence contribute to the diminished β-cell mass in PTTG–/– mice, likely secondary to DNA damage. Our results also suggest that ductal progenitor β-cells are exhausted by excessive neogenesis induced by apoptosis in PTTG–/– mice.

 
 
 
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