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Senescence Mediates Pituitary Hypoplasia and Restrains Pituitary Tumor Growth

¹ Department of Medicine, Cedars-Sinai Medical Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California and ² St. Michael's Hospital, Toronto, Ontario, Canada

Requests for reprints: Shlomo Melmed, Academic Affairs, Room 2015, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048. Phone: 310-423-4691; Fax: 310-423-0119; E-mail: melmed{at}csmc.edu.

Understanding factors subserving pituitary cell proliferation enables understanding mechanisms underlying uniquely benign pituitary tumors. Pituitary tumor-transforming gene (Pttg) deletion results in pituitary hypoplasia, low pituitary cell proliferation rates, and rescue of pituitary tumor development in Rb^+/– mice. Pttg^–/– pituitary glands exhibit ARF/p53/p21-dependent senescence pathway activation evidenced by up-regulated p19, cyclin D1, and Bcl-2 protein levels and p53 stabilization. High pituitary p21 levels in the absence of PTTG were associated with suppressed cyclin-dependent kinase 2 activity, Rb phosphorylation, and cyclin A expression, all required for cell cycle progression. Although senescence-associated ß-galactosidase was enhanced in Pttg-deficient pituitary glands, telomere lengths were increased. DNA damage signaling pathways were activated and aneuploidy was evident in the Pttg-deficient pituitary, triggering senescence-associated genes. To confirm the p21 dependency of decreased proliferation and senescence in the Pttg-null pituitary, mouse embryonic fibroblast (MEF) colony formation was tested in wild-type, Pttg^–/–, Rb^+/–, Rb^+/–Pttg^–/–, and Rb^+/–Pttg^–/–p21^–/– cells. Rb^+/–Pttg^–/– MEFs, unlike Rb^+/– cells, failed to produce colonies and exhibited high levels of senescence. p21 deletion from Rb^+/–Pttg^–/– MEFs enhanced anchorage-independent cell growth, accompanied by a marked decrease in senescence. As cell proliferation assessed by bromodeoxyuridine incorporation was higher in Rb^+/–Pttg^–/–p21^–/– relative to Rb^+/–Pttg^–/– pituitary glands, p21-dependent senescence provoked by Pttg deletion may underlie pituitary hypoplasia and decreased tumor development in Rb^+/–Pttg^–/– mice. [Cancer Res 2007;67(21):10564–72]

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