Expression of CDK4 or CDK2 in mouse oral cavity is retained in adult pituitary with distinct effects on tumorigenesis.
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 oropharynx, 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.
Macias
Everardo
E
Center for Comparative Medicine and Translational Research, Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina 27606, USA.
Miliani de Marval
Paula L
PL
Senderowicz
Adrian
A
Cullen
John
J
Rodriguez-Puebla
Marcelo L
ML
D000818:Animals; D002452:Cell Count; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009055:Mouth / Q000196:embryology / Q000201:enzymology*; D010902:Pituitary Gland / Q000201:enzymology*; D010911:Pituitary Neoplasms / Q000201:enzymology* / Q000235:genetics; D011401:Promoter Regions, Genetic; D013234:Stem Cells
C493961:Cdkn1b protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4