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UCLA School of Medicine, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Room D3066, Los Angeles, California 90048, USA

(Requests for offprints should be addressed to R Yu; Email: run.yu{at}cshs.org)

Human pituitary tumor-transforming gene 1 (PTTG1) encodes a securin protein critically important in regulating chromosome separation. Murine PTTG (mPTTG) is 66% homologous to human PTTG1 and PTTG-null (PTTG–/–) mice exhibit pancreatic ß-cell hypoplasia and abnormal nuclear morphology with resultant diabetes. As we show that ductal ß-cell neogenesis is intact in PTTG–/– mice, we explored mechanism for defective ß-cell replication. We tested whether mPTTG exhibits securin properties in mouse insulin-secreting insulinoma MIN6 cells, using a live-cell system to monitor mitosis in cells transfected with an enhanced green fluorescent protein (EGFP)-tagged mPTTG conjugate (mPTTG-EGFP). To fulfill the criteria for securin properties, the protein should undergo degradation immediately before the metaphase-to-anaphase transition when expression levels are low, and should inhibit metaphase-to-anaphase transition when expression levels are high. EGFP itself did not undergo degradation throughout mitosis and high levels of EGFP per se did not affect normal mitosis progression (n=25). However, mPTTG-EGFP was degraded 2 min before the metaphase-to-anaphase transition when expression levels were low (n=19), and high mPTTG-EGFP levels blocked metaphase-to-anaphase transition in 13 cells. mPTTG-EGFP inhibited MIN6 cell proliferation and caused apoptosis. Immunocoprecipitation demonstrated binding of mPTTG-EGFP and separase. These results show that mPTTG exhibits properties consistent with a murine securin in insulin-secreting mouse cells and mPTTG overexpression inhibits cell proliferation, suggesting that defective ß-cell proliferation observed in PTTG–/– mice is likely due to abnormal cell-cycle progression.

This article has been cited by other articles:

				V. Chesnokova, C. Wong, S. Zonis, A. Gruszka, K. Wawrowsky, S.-G. Ren, A. BenShlomo, and R. Yu Diminished Pancreatic {beta}-Cell Mass in Securin-Null Mice Is Caused by {beta}-Cell Apoptosis and Senescence Endocrinology, June 1, 2009; 150(6): 2603 - 2610. [Abstract] [Full Text] [PDF]

				F. Salehi, K. Kovacs, B. W Scheithauer, R. V Lloyd, and M. Cusimano Pituitary tumor-transforming gene in endocrine and other neoplasms: a review and update Endocr. Relat. Cancer, September 1, 2008; 15(3): 721 - 743. [Abstract] [Full Text] [PDF]