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Expression of CDK4 or CDK2 in Mouse Oral Cavity Is Retained in Adult Pituitary with Distinct Effects on Tumorigenesis

¹ Center for Comparative Medicine and Translational Research, Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina; ² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and ³ Office of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland

Requests for reprints: Marcelo L. Rodriguez-Puebla, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606. Phone: 919-515-7409; Fax: 919-515-4237; E-mail: marcelo_rodriguez-puebla{at}ncsu.edu.

The keratin 5 (K5) promoter drives transgenic expression to the basal cell layer of stratified epithelia. Surprisingly, analysis of K5CDK4 and K5CDK2 transgenic mouse embryos showed CDK4 and CDK2 expression not only in the expected tissues, but also in the adenohypophysis. This organ is derived from an upwards growth of the primitive oropharnyx, a K5-expressing tissue. We show that transgenic expression of CDKs in the embryonic oral ectoderm is specifically retained in undifferentiated cells from the pars intermedia of the adenohypophysis. Interestingly, we found that K5CDK4 mice show a decreased number of pituitary stem cells, even though CDK4 is not expressed in the stem cells but in transit-amplifying (TA)–like cells. Interestingly, CDK4-expressing cells, but not CDK2-expressing cells, strongly synergize with lack of p27^Kip1 to generate pituitary carcinomas that appear with shortened latency and are drastically more aggressive than those arising in p27^–/– mice. Thus, we show that deregulation of CDK expression in the primitive oral epithelium plays a unique function, providing a selective advantage that gives rise to transgene-positive TA-like pituitary cells. Furthermore, retention of CDK4 in these TA-like pituitary cells synergizes with loss of p27^Kip1 to induce pituitary adenocarcinomas. This model suggests that forced expression of CDK4 sensitizes cells and synergizes with a second change resulting in tumor development. [Cancer Res 2008;68(1):162–71]

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