Early G1 growth arrest of hybridoma B cells by DMSO involves cyclin D2 inhibition and p21[CIP1] induction.
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.
INSERM U364, Faculté de Médecine, Nice, France.
G
G
Ponzio
A
A
Loubat
N
N
Rochet
L
L
Turchi
R
R
Rezzonico
D
D
Farahi Far
V
V
Dulic
B
B
Rossi
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000502:physiology; D019925:Cyclin A / Q000037:antagonists & inhibitors / Q000378:metabolism; D056742:Cyclin D2; D019927:Cyclin E / Q000037:antagonists & inhibitors / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000037:antagonists & inhibitors* / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D016193:G1 Phase / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006825:Hybridomas / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D000893:Anti-Inflammatory Agents; C486196:Ccnd2 protein, mouse; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D019925:Cyclin A; D056742:Cyclin D2; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D004121:Dimethyl Sulfoxide