Activin A induction of cell-cycle arrest involves modulation of cyclin D2 and p21CIP1/WAF1 in plasmacytic cells

Mol Endocrinol. 1997 Jul;11(8):1044-52. doi: 10.1210/mend.11.8.9953.

Abstract

Activins, members of the transforming growth factor-beta 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 p21CIP1/WAF1 but had no effect on expression of cyclin-dependent kinases (CDK2, CDK4, CDK6) and other CDK inhibitors (p27KIP1, p16INK4a, p15INK4b). Modulation of cyclin D2 and p21CIP1/WAF1 expression resulted in a decrease in level of cyclin D2-CDK4 complex and an increase in level of CDK4 complexed with p21CIP1/WAF1. Moreover, overexpression of cyclin D2 partially abrogated inhibition of Rb phosphorylation and G1 arrest in the hybridoma cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins
  • Animals
  • Apoptosis / drug effects
  • CDC2-CDC28 Kinases*
  • Carrier Proteins / drug effects
  • Carrier Proteins / metabolism
  • Cell Cycle / drug effects*
  • Cell Cycle Proteins*
  • Cell Division / drug effects
  • Cyclin D2
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / drug effects
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / drug effects*
  • Cyclins / genetics
  • Cyclins / metabolism
  • G1 Phase
  • Hybridomas / drug effects
  • Inhibins / pharmacology*
  • Mice
  • Phosphorylation
  • Plasma Cells / drug effects*
  • Plasma Cells / pathology
  • Protein-Serine-Threonine Kinases / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins*
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Retinoblastoma Protein / drug effects
  • Retinoblastoma Protein / metabolism
  • Tumor Suppressor Proteins*

Substances

  • Carrier Proteins
  • Ccnd2 protein, mouse
  • Cdkn1a protein, mouse
  • Cdkn2b protein, mouse
  • Cell Cycle Proteins
  • Cyclin D2
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Retinoblastoma Protein
  • Tumor Suppressor Proteins
  • Activins
  • Inhibins
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • Cdk2 protein, mouse
  • Cdk4 protein, mouse
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases