Senescence Mediates Pituitary Hypoplasia and Restrains Pituitary Tumor Growth

Abstract 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 β-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]