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Activin A Induction of Cell-Cycle Arrest Involves Modulation of Cyclin D2 and p21^CIP1/WAF1 in Plasmacytic Cells

Department of Oral Science (K.Y., T.K., M.O., T.N.) The National Institute of Infectious Diseases Tokyo 162, Japan,
Department of Molecular Cellular Oncology/Microbiology (K.Y.) Faculty of Dentistry Tokyo Medical and Dental University Tokyo 113, Japan
Division of Hematology (M.K., Y.I.) Keio University Medical School Tokyo 160, Japan

Activins, members of the transforming growth factor-ß family, have been implicated in the regulation of growth and differentiation of various types of cells. We have recently found that activin A induces apoptotic cell death of plasmacytic cells including B cell hybridoma cells and myeloma cells. In the present study, we demonstrated that activin A caused cell-cycle arrest in the G1 phase before appearance of apoptotic cells in mouse B cell hybridoma cells. Phosphorylation of retinoblastoma protein (Rb) and in vitro Rb kinase activity of cyclin-dependent kinase (CDK)4 was inhibited in activin A-treated cells. Analysis of expression of genes regulating Rb phosphorylation revealed that activin A suppressed cyclin D2, the sole D-type cyclin gene expressed in the hybridoma cells, and activated p21^CIP1/WAF1 but had no effect on expression of cyclin-dependent kinases (CDK2, CDK4, CDK6) and other CDK inhibitors (p27^KIP1, p16^INK4a, p15^INK4b). Modulation of cyclin D2 and p21^CIP1/WAF1 expression resulted in a decrease in level of cyclin D2-CDK4 complex and an increase in level of CDK4 complexed with p21^CIP1/WAF1. Moreover, overexpression of cyclin D2 partially abrogated inhibition of Rb phosphorylation and G1 arrest in the hybridoma cells.

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