Reduced expression levels of the cell-cycle inhibitor p27Kip1 in human pituitary adenomas

IHF Institute for Hormone and Fertility Research, University of Hamburg, Germany.

The molecular mechanisms leading to increased cellular proliferation rates and, thus, tumor formation in the anterior pituitary gland are poorly understood. The cyclin-dependent kinase inhibitor p27Kip1 is a key molecule regulating the G1 phase of the cell cycle in many cell types. Furthermore, it was shown that p27 knock-out mice develop pro-opiomelanocortin-positive pituitary tumors. In an effort to clarify the role of p27 in the normal and tumorous human pituitary, we studied the expression of p27 by immunohistochemistry, using a highly specific mouse monoclonal anti-human p27 antibody. Normal pituitaries and 54 pituitary adenomas (twelve somatotrope adenomas, nine prolactinomas, twelve corticotrope adenomas, three TSH-producing tumors, six gonadotrope adenomas, six null cell adenomas, and six oncocytomas) were analyzed. p27 expression was determined semiquantitatively with regard to both the percentage of positive cells and the intensity of the staining. Normal human pituitaries showed strong expression of p27 in most nuclei. In contrast, the levels of p27 were reduced in the majority of the tumors analyzed. Twenty-two tumors (six somatotrope adenomas, five prolactinomas, four corticotrope adenomas, two TSH-producing tumors, two gonadotrope adenomas, and three null cell adenomas) were completely p27-negative. In 18 tumors, p27 expression was found in < or = 10% of the cells. In the other ten tumors, 11-80% of the cells were p27-positive. In summary, we were able to demonstrate reduced expression levels of the cell-cycle inhibitor p27 in tumors derived from all pituitary cell types. Our data indicate that p27 may be an important regulator of cellular proliferation in the anterior pituitary, the underexpression of which could play a role in pituitary tumorigenesis.

This article has been cited by other articles:

				M. Grant, H. Alturaihi, P. Jaquet, B. Collier, and U. Kumar Cell Growth Inhibition and Functioning of Human Somatostatin Receptor Type 2 Are Modulated by Receptor Heterodimerization Mol. Endocrinol., October 1, 2008; 22(10): 2278 - 2292. [Abstract] [Full Text] [PDF]

				X. Zhu, X. Mao, R. Hurren, A. D. Schimmer, S. Ezzat, and S. L. Asa Deoxyribonucleic Acid Methyltransferase 3B Promotes Epigenetic Silencing through Histone 3 Chromatin Modifications in Pituitary Cells J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3610 - 3617. [Abstract] [Full Text] [PDF]

				X. Zhu, S. L. Asa, and S. Ezzat Fibroblast Growth Factor 2 and Estrogen Control the Balance of Histone 3 Modifications Targeting MAGE-A3 in Pituitary Neoplasia Clin. Cancer Res., April 1, 2008; 14(7): 1984 - 1996. [Abstract] [Full Text] [PDF]

				M. Georgitsi, A. Raitila, A. Karhu, R. B. van der Luijt, C. M. Aalfs, T. Sane, O. Vierimaa, M. J. Makinen, K. Tuppurainen, R. Paschke, et al. Germline CDKN1B/p27Kip1 Mutation in Multiple Endocrine Neoplasia J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3321 - 3325. [Abstract] [Full Text] [PDF]

				X. Zhu, K. Lee, S. L. Asa, and S. Ezzat Epigenetic Silencing through DNA and Histone Methylation of Fibroblast Growth Factor Receptor 2 in Neoplastic Pituitary Cells Am. J. Pathol., May 1, 2007; 170(5): 1618 - 1628. [Abstract] [Full Text] [PDF]

				E. Hubina, A. M Nanzer, M. R Hanson, E. Ciccarelli, M. Losa, D. Gaia, M. Papotti, M. R. Terreni, S. Khalaf, S. Jordan, et al. Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours. Eur. J. Endocrinol., August 1, 2006; 155(2): 371 - 379. [Abstract] [Full Text] [PDF]

				M Musat, M Korbonits, B Kola, N Borboli, M R Hanson, A M Nanzer, J Grigson, S Jordan, D G Morris, M Gueorguiev, et al. Enhanced protein kinase B/Akt signalling in pituitary tumours Endocr. Relat. Cancer, June 1, 2005; 12(2): 423 - 433. [Abstract] [Full Text] [PDF]

				A. Lania, G. Mantovani, and A. Spada Genetics of Pituitary Tumors: Focus on G-Protein Mutations Experimental Biology and Medicine, October 1, 2003; 228(9): 1004 - 1017. [Abstract] [Full Text] [PDF]

				M. Korbonits, H. S. Chahal, G. Kaltsas, S. Jordan, Y. Urmanova, Z. Khalimova, P. E. Harris, W. E. Farrell, F.-X. Claret, and A. B. Grossman Expression of Phosphorylated p27Kip1 Protein and Jun Activation Domain-Binding Protein 1 in Human Pituitary Tumors J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2635 - 2643. [Abstract] [Full Text] [PDF]

				A. M. Mirza, A. D. Kohn, R. A. Roth, and M. McMahon Oncogenic Transformation of Cells by a Conditionally Active Form of the Protein Kinase Akt/PKB Cell Growth Differ., June 1, 2000; 11(6): 279 - 292. [Abstract] [Full Text]