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Genetic mosaics reveal both cell-autonomous and cell-nonautonomous function of murine p27 Kip1

Genetic mosaics reveal both cell-autonomous and cell-nonautonomous function of murine p27 Kip1
Loss of the cyclin-dependent kinase inhibitor p27 Kip1 leads to an overall increase in animal growth, pituitary tumors, and hyperplasia of hematopoietic organs, yet it is unknown whether all cells function autonomously in response to p27 Kip1 activity or whether certain cells take cues from their neighbors. In addition, there is currently no genetic evidence that tumor suppression by p27 Kip1 is cell-autonomous because biallelic gene inactivation is absent from tumors arising in p27 Kip1 hemizygous mice. We have addressed these questions with tissue-specific targeted mouse mutants and radiation chimeras. Our results indicate that the suppression of pars intermedia pituitary tumors by p27 Kip1 is cell-autonomous and does not contribute to overgrowth or infertility phenotypes. In contrast, suppression of spleen growth and hematopoietic progenitor expansion is a consequence of p27 Kip1 function external to the hematopoietic compartment. Likewise, p27 Kip1 suppresses thymocyte hyperplasia through a cell-nonautonomous mechanism. The interaction of p27 Kip1 loss with epithelial cell-specific cyclin-dependent kinase 4 overexpression identifies the thymic epithelium as a relevant site of p27 Kip1 activity for the regulation of thymus growth.
- University of North Carolina at Chapel Hill United States
- Clinical Research Division Fred Hutchinson Cancer Research Center United States
- South Carolina State University United States
- Fred Hutchinson Cancer Research Center South Africa
- UNC Lineberger Comprehensive Cancer Center United States
Male, Mice, Knockout, Hyperplasia, Base Sequence, Mosaicism, Mice, Transgenic, DNA, Thymus Gland, Mice, Pituitary Gland, Radiation Chimera, Mutation, Animals, Female, Pituitary Neoplasms, Cyclin-Dependent Kinase Inhibitor p27, Spleen
Male, Mice, Knockout, Hyperplasia, Base Sequence, Mosaicism, Mice, Transgenic, DNA, Thymus Gland, Mice, Pituitary Gland, Radiation Chimera, Mutation, Animals, Female, Pituitary Neoplasms, Cyclin-Dependent Kinase Inhibitor p27, Spleen
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