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Articles by K Wawrowsky
Total Records ( 2 ) for K Wawrowsky
  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.

  C Zhou , K Wawrowsky , S Bannykh , S Gutman and S. Melmed
 

Rb/E2F is dysregulated in murine and human pituitary tumors. Pituitary tumor transforming gene (PTTG1), a securin protein, is required for pituitary tumorigenesis, and PTTG1 deletion attenuates pituitary tumor development in Rb+/– mice. E2F1 and PTTG1 were concordantly overexpressed in 29 of 46 Rb+/– murine pituitary tissues and also in 45 of 80 human pituitary tumors (P < 0.05). E2F1 specifically bound the hPTTG1 promoter as assessed by chromatin immunoprecipitation and biotin-streptavidin pull-down assay, indicating that hPTTG1 may act as a direct E2F1 target. Transfection of E2F1 and its partner DP1 dose-dependently activated hPTTG1 transcription up to 3-fold in p53-devoid H1299 cells but not in p53-replete HCT116 cells. E2F1 overexpression enhanced endogenous hPTTG1 mRNA and protein levels up to 3-fold in H1299 cells. The presence of endogenous p53/p21 constrained the induction, whereas knocking down either p53 or p21 in HCT116 cells restored E2F1-induced hPTTG1 transactivation and expression. Moreover, suppressing Rb by small interfering RNA concordantly elevated E2F1 and hPTTG1 protein levels. In contrast, transfection of E2F1 small interfering RNA lowered hPTTG1 levels 24 h later in HCT116 than in H1299 cells, indicating that p53 delays E2F1 action on hPTTG1. These results elucidate a mechanism for abundant tumor hPTTG1 expression, whereby Rb inactivation releases E2F1 to induce hPTTG1. This signaling pathway may underlie the requirement of PTTG1 for pituitary tumorigenesis.

 
 
 
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