title: p27Kip1 and p130 cooperate to regulate hematopoietic cell proliferation in vivo.
abstract: 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.
authors.affiliation: Department of Oncology and Cancer Research UK Labs, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
authors.forename: Inês
authors.initials: I
authors.lastname: Soeiro
authors.forename: Azim
authors.initials: A
authors.lastname: Mohamedali
authors.forename: Hanna M
authors.initials: HM
authors.lastname: Romanska
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Lea
authors.forename: Emma S
authors.initials: ES
authors.lastname: Child
authors.forename: Janet
authors.initials: J
authors.lastname: Glassford
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Orr
authors.forename: Claudia
authors.initials: C
authors.lastname: Roberts
authors.forename: Kikkeri N
authors.initials: KN
authors.lastname: Naresh
authors.forename: El-Nasir
authors.initials: el-N
authors.lastname: Lalani
authors.forename: David J
authors.initials: DJ
authors.lastname: Mann
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Watson
authors.forename: N Shaun B
authors.initials: NS
authors.lastname: Thomas
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
mesh_terms: 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
chemical_list: 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