Genetic mosaics reveal both cell-autonomous and cell-nonautonomous function of murine p27Kip1.

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. [ABSTRACT FROM AUTHOR]