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Molecular Endocrinology 15 (11): 1870-1879
Copyright © 2001 by The Endocrine Society

Mice Lacking Pituitary Tumor Transforming Gene Show Testicular and Splenic Hypoplasia, Thymic Hyperplasia, Thrombocytopenia, Aberrant Cell Cycle Progression, and Premature Centromere Division

Zhiyong Wang, Run Yu and Shlomo Melmed

Department of Medicine, Cedars-Sinai Research Institute, University of California Los Angeles School of Medicine, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Shlomo Melmed, M.D., Research Institute, Room 2015, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. E-mail: melmed{at}csmc.edu

Tumorigenic pituitary tumor transforming gene (PTTG) is a mammalian homolog of Xenopus securin that inhibits chromatid separation, is overexpressed in many human tumor types, and mediates transcriptional activation. Loss of yeast securin Pds1p or Drosophila securin pimples is lethal. Here we show that mice lacking PTTG (PTTG -/-) are, surprisingly, viable and fertile; but they have testicular and splenic hypoplasia, thymic hyperplasia, and thrombocytopenia. PTTG -/- mouse embryo fibroblasts exhibited aberrant cell cycle progression with prolonged G2-M phase and binucleated and multinucleated nuclei with increased aneuploidy. PTTG -/- mouse embryo fibroblast metaphases contained quadriradial, triradial, and chromosome breaks, as well as premature centromere division. The results show that PTTG functions to maintain chromosome stability, cell cycle progression, and appropriate cell division. Moreover, mammalian sister chromatid separation, an important transition in the cell cycle, is likely regulated by mechanisms in addition to securin.




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