Senescence mediates pituitary hypoplasia and restrains pituitary tumor growth.
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 beta-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.
Chesnokova
Vera
V
Department of Medicine, Cedars-Sinai Medical Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90048, USA.
Zonis
Svetlana
S
Rubinek
Tami
T
Yu
Run
R
Ben-Shlomo
Anat
A
Kovacs
Kalman
K
Wawrowsky
Kolja
K
Melmed
Shlomo
S
D000375:Aging; D000782:Aneuploidy; D000818:Animals; D002453:Cell Cycle; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D004249:DNA Damage; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000502:physiology*; D009929:Organ Size; D010902:Pituitary Gland / Q000473:pathology*; D010911:Pituitary Neoplasms / Q000517:prevention & control*; D011401:Promoter Regions, Genetic; D016160:Retinoblastoma Protein / Q000502:physiology; D064249:Securin; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000502:physiology; D016615:Telomere; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009363:Neoplasm Proteins; D016160:Retinoblastoma Protein; D064249:Securin; D016329:Sp1 Transcription Factor; D016159:Tumor Suppressor Protein p53