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

Abstract

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.cell cycle ͉ cyclin-dependent kinase inhibitor ͉ growth genetics ͉ pituitary tumor ͉ thymus development

Rb is dispensable for self-renewal and multilineage differentiation of adult hematopoietic stem cells

“…They demonstrate that the lymphoid expansion in the p27 Kip1Ϫ/Ϫ animals is not intrinsic to the hematopoietic cells, raising the possibility that the expanded HSC population reported in ref. 3 is actually the result of a microenvironment defect or of non-cell cycle regulatory roles of p27 Kip1 (31,32). This result is particularly interesting because we observed subtle changes in hematopoiesis after the specific deletion of Rb in the adult HSC, raising the possibility that a significant proportion of the role attributed to cell cycle regulation in HSC self-renewal and differentiation may be mediated by the microenvironment or niche.…”

“…Chien et al (31) have recently reported that transplantation of wild-type bone marrow into a p27 Kip1Ϫ/Ϫ environment͞niche resulted in an expansion of lymphoid cells to a level comparable with that observed in the p27 Kip1Ϫ/Ϫ mutant itself. They demonstrate that the lymphoid expansion in the p27 Kip1Ϫ/Ϫ animals is not intrinsic to the hematopoietic cells, raising the possibility that the expanded HSC population reported in ref.…”

Discovery of an oncogenic activity in p27Kip1that causes stem cell expansion and a multiple tumor phenotype

“…In contrast, spontaneous lung tumors were very infrequent in p27-null mice. A previously reported cohort of 34 p27-null mice had a zero incidence of lung tumors when sacrificed at Ն7 mo of age (Chien et al 2006). Similarly to adrenal hyperplasia, ovarian hyperplasia, and T-cell lymphomagenesis, the lung tumor phenotype was genetically dominant, as 46% of p27 +/CK − also developed lung adenomas and carcinomas by 12 mo of age (Table 1B).…”

Interweaving the Cell Cycle Machinery with Cell Differentiation

“…27 Transplantation might be the ideal way to establish cell autonomous behavior, however, there are other approaches that can substitute. For example, lineage specific expression using conditional alleles, 28 or studying the differentiation of the cell in culture following its isolation from mice are both reasonable surrogates to transplantation. Regardless of how one might establish cell autonomous behavior, a differentiation phenotype can represent different defects, including those in cell cycle exit, the maintenance of quiescence, or in the transcriptional program accompanying differentiation.…”