Abstract
Dimethylsulfoxide (DMSO) was shown to inhibit the proliferation of several B cell lines including Raji, Daudi, and SKW6-CL4 but the mechanisms involved in this growth arrest are still unclear. We show that in 7TD1 mouse hybridoma cells a DMSO-induced reversible G1 arrest involves 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 accumulation of p21[CIP1] entails increasing association with cyclin D3/CDK4 and cyclin E/CDK2. Thus, p21[CIP1] and p27[KIP1], act in concert to inhibit cyclin E/CDK2 activity which, together with CDK4 inactivation, confers a G1-phase arrest.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Administration, Topical
-
Animals
-
Anti-Inflammatory Agents / pharmacology*
-
B-Lymphocytes / cytology
-
B-Lymphocytes / drug effects*
-
B-Lymphocytes / physiology
-
CDC2-CDC28 Kinases*
-
Cell Cycle Proteins*
-
Cell Division / physiology
-
Cyclin A / antagonists & inhibitors
-
Cyclin A / metabolism
-
Cyclin D2
-
Cyclin E / antagonists & inhibitors
-
Cyclin E / metabolism
-
Cyclin-Dependent Kinase 2
-
Cyclin-Dependent Kinase 4
-
Cyclin-Dependent Kinase Inhibitor p21
-
Cyclin-Dependent Kinase Inhibitor p27
-
Cyclin-Dependent Kinases / antagonists & inhibitors
-
Cyclin-Dependent Kinases / metabolism
-
Cyclins / antagonists & inhibitors*
-
Cyclins / drug effects*
-
Cyclins / genetics
-
Cyclins / metabolism
-
Dimethyl Sulfoxide / pharmacology*
-
G1 Phase / physiology*
-
Gene Expression / drug effects
-
Gene Expression Regulation / drug effects
-
Hybridomas / cytology
-
Hybridomas / drug effects
-
Hybridomas / physiology
-
Mice
-
Microtubule-Associated Proteins / drug effects
-
Microtubule-Associated Proteins / genetics
-
Phosphorylation / drug effects
-
Protein Serine-Threonine Kinases / antagonists & inhibitors
-
Protein Serine-Threonine Kinases / metabolism
-
Proto-Oncogene Proteins*
-
Retinoblastoma Protein / metabolism
-
Tumor Suppressor Proteins*
Substances
-
Anti-Inflammatory Agents
-
Ccnd2 protein, mouse
-
Cdkn1a protein, mouse
-
Cdkn1b protein, mouse
-
Cell Cycle Proteins
-
Cyclin A
-
Cyclin D2
-
Cyclin E
-
Cyclin-Dependent Kinase Inhibitor p21
-
Cyclins
-
Microtubule-Associated Proteins
-
Proto-Oncogene Proteins
-
Retinoblastoma Protein
-
Tumor Suppressor Proteins
-
Cyclin-Dependent Kinase Inhibitor p27
-
Protein Serine-Threonine Kinases
-
CDC2-CDC28 Kinases
-
Cdk2 protein, mouse
-
Cdk4 protein, mouse
-
Cyclin-Dependent Kinase 2
-
Cyclin-Dependent Kinase 4
-
Cyclin-Dependent Kinases
-
Dimethyl Sulfoxide