Genetic Mosaics Reveal Both Cell-Autonomous and Cell-Nonautonomous Function of Murine$p27^{Kip1}

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-03, Vol.103 (11), p.4122-4127
• Main Authors: Chien, Wei-Ming, Rabin, Stuart, Macias, Everardo, de Marval, Paula L. Miliani, Garrison, Kendra, Orthel, Jason, Rodriguez-Puebla, Marcelo, Fero, Matthew L.
• Format: Article
• Language: English
• Subjects: Alleles; Cell growth; Cyclins; Genetic mutation; Lymphocytes; Mice; Pituitary neoplasms; T lymphocytes; Transgenic animals; Tumors
• ISSN: 0027-8424
• DOI: 10.1073/pnas.0509514103

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 cyclindependent kinase 4 overexpression identifies the thymic epithelium as a relevant site of$p27^{Kip1}$activity for the regulation of thymus growth.