Cyclin D1 regulates p27(Kip1) stability in B cells.
p27(Kip1) is a cyclin-dependent kinase inhibitor that plays a critical role in regulating G(1)/S transition, and whose activity is, in part, regulated through interactions with D-type cyclins. We have generated the BD1-9 cell line, a BaF3 pro-B cells derivative in which cyclin D1 can be induced rapidly and reversibly by ponasterone A. The induction of cyclin D1 expression leads to a targeted p27(Kip1) accumulation in both cytoplasmic and nuclear compartments. But, only the p27(Kip1) form phosphorylated on serine 10 (pSer10-p27(Kip1)) accumulates in BD1-9 cells. We found that the binding of cyclin D1 and pSer10-p27(Kip1) prevents p27(Kip1) degradation by the cytoplasmic Kip1 ubiquitylation-promoting complex (KPC) proteosomic pathway. Importantly, the nuclear CDK2 activity which is crucial for G(1)/S transition is not altered by p27(Kip1) increase. Using siRNA techniques, we revealed that p27(Kip1) inhibition does not affect the distribution of BD1-9 cells in the different phases of the cell cycle. Our study demonstrates that aberrant cyclin D1 expression acts as a p27(Kip1) trap in B lymphocytes but does not induce p27(Kip1) relocation from the nucleus to the cytoplasm and does not modulate the G(1)/S transition. Since our cellular model mimics what observed in aggressive lymphomas, our data bring new insights into the understanding of their physiopathology.
Bustany
Sophie
S
Biologie Moléculaire et Cellulaire de la Signalisation, EA 3919, IFR ICORE, Université de Caen Basse-Normandie, Caen Cedex, France. sophie.bustany@aliceadsl.fr
Tchakarska
Guergana
G
Sola
Brigitte
B
D000818:Animals; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004441:Ecdysterone / Q000031:analogs & derivatives / Q000494:pharmacology; D016193:G1 Phase; D051379:Mice; D010766:Phosphorylation; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology / Q000378:metabolism*; D055550:Protein Stability; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016196:S Phase
D034741:RNA, Small Interfering; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004441:Ecdysterone; C008999:ponasterone A; D051358:Cyclin-Dependent Kinase 4