Data from Senescence Mediates Pituitary Hypoplasia and Restrains Pituitary Tumor Growth

<div>Abstract<p>Understanding factors subserving pituitary cell proliferation enables understanding mechanisms underlying uniquely benign pituitary tumors. Pituitary tumor-transforming gene (<i>Pttg</i>) deletion results in pituitary hypoplasia, low pituitary cell proliferation rates, and rescue of pituitary tumor development in <i>Rb^+/−</i> mice. <i>Pttg^−/−</i> 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 <i>Pttg</i>-deficient pituitary glands, telomere lengths were increased. DNA damage signaling pathways were activated and aneuploidy was evident in the <i>Pttg</i>-deficient pituitary, triggering senescence-associated genes. To confirm the p21 dependency of decreased proliferation and senescence in the <i>Pttg</i>-null pituitary, mouse embryonic fibroblast (MEF) colony formation was tested in wild-type, <i>Pttg^−/−, Rb^+/−, Rb^+/−Pttg^−/−</i>, and <i>Rb^+/−Pttg^−/−p21^−/−</i> cells. <i>Rb^+/−Pttg^−/−</i> MEFs, unlike <i>Rb^+/−</i> cells, failed to produce colonies and exhibited high levels of senescence. p21 deletion from <i>Rb^+/−Pttg^−/−</i> MEFs enhanced anchorage-independent cell growth, accompanied by a marked decrease in senescence. As cell proliferation assessed by bromodeoxyuridine incorporation was higher in <i>Rb^+/−Pttg^−/−p21^−/−</i> relative to <i>Rb^+/−Pttg^−/−</i> pituitary glands, p21-dependent senescence provoked by <i>Pttg</i> deletion may underlie pituitary hypoplasia and decreased tumor development in <i>Rb^+/−Pttg^−/−</i> mice. [Cancer Res 2007;67(21):10564–72]</p></div>