p21(Cip1) restrains pituitary tumor growth.
As commonly encountered, pituitary adenomas are invariably benign. We therefore studied protective pituitary proliferative mechanisms. Pituitary tumor transforming gene (Pttg) deletion results in pituitary p21 induction and abrogates tumor development in Rb(+/-)Pttg(-/-) mice. p21 disruption restores attenuated Rb(+/-)Pttg(-/-) pituitary proliferation rates and enables high penetrance of pituitary, but not thyroid, tumor growth in triple mutant animals (88% of Rb(+/-) and 72% of Rb(+/-)Pttg(-/-)p21(-/-) vs. 30% of Rb(+/-)Pttg(-/-) mice developed pituitary tumors, P < 0.001). p21 deletion also accelerated S-phase entry and enhanced transformation rates in triple mutant MEFs. Intranuclear p21 accumulates in Pttg-null aneuploid GH-secreting cells, and GH(3) rat pituitary tumor cells overexpressing PTTG also exhibited increased levels of mRNA for both p21 (18-fold, P < 0.01) and ATM (9-fold, P < 0.01). PTTG is abundantly expressed in human pituitary tumors, and in 23 of 26 GH-producing pituitary adenomas with high PTTG levels, senescence was evidenced by increased p21 and SA-beta-galactosidase. Thus, either deletion or overexpression of Pttg promotes pituitary cell aneuploidy and p53/p21-dependent senescence, particularly in GH-secreting cells. Aneuploid pituitary cell p21 may constrain pituitary tumor growth, thus accounting for the very low incidence of pituitary carcinomas.
Chesnokova
Vera
V
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Zonis
Svetlana
S
Kovacs
Kalman
K
Ben-Shlomo
Anat
A
Wawrowsky
Kolja
K
Bannykh
Serguei
S
Melmed
Shlomo
S
D000782:Aneuploidy; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009363:Neoplasm Proteins / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D064249:Securin; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D064249:Securin; D025521:Tumor Suppressor Proteins; C578002:pituitary tumor-transforming protein 1, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases