Models of tumor suppression by cell cycle growth inhibitors commonly assume that the critical inhibitory activity is intrinsic to the tumor clone. The recent discovery of tumor suppressor genes which are incapable of fully suppressing neoplastic growth with loss of only a single gene copy (i.e. haploid insufficient tumor suppression) in mouse models raises the possibility of alternative, non cell-autonomous mechanisms of tumor suppression. For example, loss of cell cycle inhibitor expression in cells extrinsic to the neoplastic clone may enhance cell growth by signals mediated through extracellular contact, paracrine factors, or angiogenesis. This project will further our understanding of the mechanism of tumor suppression by the CDK inhibitor p27Kipl and several interacting molecules. The studies will create targeted mutations in the mouse in which p27 is either deleted or activated in specific tissues. These novel gene mutations will then be combined with well defined murine models of induced carcinogenesis and gene expression analysis to define the mechanism of tumor suppression of p27 and its biochemical effects in tumorigenesis. By developing mice which harbor cell cycle gene mutations confined to the pituitary or thymus it will be determined whether the p27Kip 1 can induce adenomas and lymphomas in these tissues in a cell autonomous fashion, that is independent of the influence of factors from surrounding cells or tissues. In each model system the mechanism of tumor suppression by p27 will be further defined and the patterns of altered gene expression and cell cycle protein function will be characterized. In order to treat cancer with inhibitors of cyclin dependent kinases it is essential to identify the appropriate target cell population. Inhibition of tumorigenesis by targeting growth of normal cell populations may have the advantage of being more predictable and less prone to escape by mutations in the tumor clone.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Yassin, Rihab R,
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Kuppers, Daniel A; Schmitt, Thomas M; Hwang, Harry C et al. (2017) The miR-106a~363Xpcl1 miRNA cluster induces murine T cell lymphoma despite transcriptional activation of the p27Kip1 cell cycle inhibitor. Oncotarget 8:50680-50691
Hatton, Beryl A; Ellison, David W; Gajjar, Amar et al. (2013) Prognostic value and functional consequences of cell cycle inhibitor p27Kip1 loss in medulloblastoma. Biomark Res 1:14
Jatzek, Anna; Marie Tejera, Melba; Plisch, Erin H et al. (2013) T-cell intrinsic and extrinsic mechanisms of p27Kip1 in the regulation of CD8 T-cell memory. Immunol Cell Biol 91:120-9
Kuppers, Daniel A; Hwang, Harry C; Jackson, Aimee L et al. (2011) Effect of Xpcl1 activation and p27(Kip1) loss on gene expression in murine lymphoma. PLoS One 6:e14758
Oesterle, Elizabeth C; Chien, Wei-Ming; Campbell, Sean et al. (2011) p27(Kip1) is required to maintain proliferative quiescence in the adult cochlea and pituitary. Cell Cycle 10:1237-48
Chien, Wei-Ming; Garrison, Kendra; Caufield, Emily et al. (2007) Differential gene expression of p27Kip1 and Rb knockout pituitary tumors associated with altered growth and angiogenesis. Cell Cycle 6:750-7