p27Kip1 and p130 cooperate to regulate hematopoietic cell proliferation in vivo.
To investigate the potential functional cooperation between p27Kip1 and p130 in vivo, we generated mice deficient for both p27Kip1 and p130. In p27Kip1-/-; p130-/- mice, the cellularity of the spleens but not the thymi is significantly increased compared with that of their p27Kip1-/- 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 p27Kip1-/-; p130-/- animals. Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence of p27Kip1 in binding to and repressing CDK2 and is the predominant CDK-inhibitor associated with the inactive CDK2 in the p27Kip1-/- splenocytes. The finding that the p27Kip1-/-; 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 p27Kip1 to regulate hematopoietic cell proliferation in vivo.
Soeiro
Inês
I
Department of Oncology and Cancer Research UK Labs, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
Mohamedali
Azim
A
Romanska
Hanna M
HM
Lea
Nicholas C
NC
Child
Emma S
ES
Glassford
Janet
J
Orr
Stephen J
SJ
Roberts
Claudia
C
Naresh
Kikkeri N
KN
Lalani
El-Nasir
el-N
Mann
David J
DJ
Watson
Roger J
RJ
Thomas
N Shaun B
NS
Lam
Eric W-F
EW
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D001789:Blood Group Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000378:metabolism*; D006413:Hematopoietic System / Q000166:cytology*; D017493:Leukocyte Common Antigens / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D050717:Retinoblastoma-Like Protein p130 / Q000172:deficiency / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics
D001789:Blood Group Antigens; D017252:CD3 Complex; C493838:Rbl2 protein, mouse; D050717:Retinoblastoma-Like Protein p130; C489122:TER-119 antigen, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051357:Cyclin-Dependent Kinase 2; D017493:Leukocyte Common Antigens