EARLY G(1) GROWTH ARREST OF HYBRIDOMA B-CELLS BY DMSO INVOLVES CYCLIND2 INHIBITION AND P21([CIP1]) INDUCTION

Dimethylsulfoxide (DMSO) was shown to inhibit the proliferation of sev eral B cell lines including Raji, Daudi, and SKW6-CL4 but the mechanis ms involved in this growth arrest are still unclear. We show that in 7 TD1 mouse hybridoma cells a DMSO-induced reversible G(1) arrest involv es inactivation of Rb kinases, cyclin D2/CDK4 and cyclin E/CDK2. This occurs by at least three distinct mechanisms. Inhibition of cyclin D2 neosynthesis leads to a dramatic decrease of cyclinD2/CDK4 complexes. This in turn enables the redistribution of p27([KIP1]) from cyclin D2/ CDK4 to cyclin E/CDK2 complexes. In addition, the simultaneous accumul ation of p21([CIP1]) entails increasing association with cyclin D3/CDK 4 and cyclin E/CDK2. Thus, p21([CIP1]) and p27([KIP1]), act in concert to inhibit cyclin E/CDK2 activity which, together with CDK4 inactivat ion, confers a G(1)-phase arrest.