p27^Kip1 and p130 cooperate to regulate hematopoietic cell proliferation in vivo

To investigate the potential functional cooperation between p27 ^Kip1 and p130 in vivo, we generated mice deficient for both p27 ^Kip1 and p130. In p27^Kip1-/-;o130^-/- mice, the cellularity of the spleens but not the thymi is significantly increased compared with that of their p27^Kip1-/- counterparts, affecting the lymphoid, erythroid, and myeloid compartments. In vivo cell proliferation is significantly augmented in the B and T cells, monocytes, macrophages, and erythroid progenitors in the spleens of p27^Kip1-/-;p130^-/- animals. Immunoprecipitation and immunodepletion studies indicate that pl30 can compensate for the absence of p27^Kip1 in binding to and repressing CDK2 and is the predominant CDK-inhibitor associated with the inactive CDK2 in the p27^Kip1-/- splenocytes. The finding that the p27 ^Kip1-/-; p130^-/- splenic B cells are hypersensitive to mitogenic stimulations in vitro lends support to the concept that the hyperproliferation of splenocytes is not a result of the influence of their microenvironment. In summary, our findings provide genetic and molecular evidence to show that p130 is a bona fide cyclin-dependent kinase inhibitor and cooperates with p27^Kip1 to regulate hematopoietic cell proliferation in vivo.