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.
Chien
Wei-Ming
WM
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Rabin
Stuart
S
Macias
Everardo
E
Miliani de Marval
Paula L
PL
Garrison
Kendra
K
Orthel
Jason
J
Rodriguez-Puebla
Marcelo
M
Fero
Matthew L
ML
D000818:Animals; D001483:Base Sequence; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000502:physiology*; D004247:DNA / Q000235:genetics; D005260:Female; D006965:Hyperplasia; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009030:Mosaicism; D009154:Mutation; D010902:Pituitary Gland / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology; D011828:Radiation Chimera; D013154:Spleen / Q000473:pathology; D013950:Thymus Gland / Q000473:pathology
C493961:Cdkn1b protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA