The Cyclin Interactor p26INCA1 Regulates the Hematopoietic Stem Cell Pool Via CDK Inhibition.

摘要: Cell cycle progression is driven by the kinase activity of cyclin/CDK complexes. Dysregulation cell leads to altered growth and contributes tumorigenesis. Recently, we identified p26 INCA1 as novel interaction partner Cyclin A1/CDK2. Here, characterize phenotype Inca1 -null mice uncover cellular molecular function Inca1. -knockout were viable fertile. FACS analyses revealed that aging mutant animals harbored an increased hematopoietic stem (HSC) pool. Bone marrow cells young exhibited enhanced clonogenic replating efficiency in colony formation assays compared wildtype mice. Weekly administration myeloablative agent 5-fluorouracil (5-FU) led a significantly shorter life span −/ − littermates. The 5-FU toxicity might thus be related higher number cycling HSC bone marrow. Analysis impact on regulation demonstrated fraction embryonic fibroblasts (MEFs) S phase was increased. Ectopic expression reduced proliferation proliferating such primary cells, HeLa, HuTu80 32D lines. Serum starvation rapidly induced mitogenic signals inhibited providing further link regulation. To identify mechanism Inca1, investigated influence direct inhibition CDK2. In spleen lysates from -deficient mice, CDK2 towards Histone H1 vitro assays, recombinant strongly activity. addition, hypothesized other cyclin inhibitors (CKI) could partially compensate vivo for loss function. p21 cip1/waf1 mRNA protein MEFs hinting at partial compensation induction . Loss combined with knockdown synergistically S-phase. These results indicate functionally rather mild observed modest differences Cdk lacking due compensatory CKI p21. summary, proliferation, efficiency, S-phase progression, Cdk2 whereas gain suppressed these functions. during arrest. We conclude suppressor regulating quiescence HSCs through Cdk2.