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p21(Cip1) restrains pituitary tumor growth.

Authors: Chesnokova, V  Zonis, S  Kovacs, K  Ben-Shlomo, A  Wawrowsky, K  Bannykh, S  Melmed, S 
Citation: Chesnokova V, etal., Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17498-503. doi: 10.1073/pnas.0804810105. Epub 2008 Nov 3.
Pubmed: (View Article at PubMed) PMID:18981426
DOI: Full-text: DOI:10.1073/pnas.0804810105

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.

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CRRD Object Information
CRRD ID: 8662821
Created: 2014-06-25
Species: All species
Last Modified: 2014-06-25
Status: ACTIVE



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