Cyclin D-cdk6 complex is targeted by p21(WAF) in growth-arrested lymphoma cells.
Normal human B lymphocytes are sensitive to the growth-inhibitory action of transforming growth factor beta1 (TGFbeta1) whereas malignant B lymphoma cells are mostly resistant to TGFbeta1 effects. We examined the phosphorylation status of retinoblastoma protein and the activity of G(1) cyclin-dependent kinases (cdk) in TGFbeta1-sensitive malignant follicular lymphoma cells during the TGFbeta1 treatment. The kinase activity of cdk2, cdk4, and cdk6 was significantly reduced and hypophosphorylation of pRb on serine 795 (S795) and threonine 373 (T373) was observed. We examined the composition of cdk complexes and the level of cdk inhibitors to explain the inhibitory action of TGFbeta1 toward cdk activity. Both cdk4 and cdk6 were notably dissociated from cyclin D cofactors, while cyclin E-cdk2 complexes remained coupled in TGFbeta1-treated cells. TGFbeta1-induced growth arrest was associated with notably increased binding of p21(WAF1) to cdk4 and cdk6. No induction of cdk-inhibitor molecules of INK family was observed in TGFbeta1-treated DoHH2 cells. As shown, TGFbeta1-induced growth arrest of malignant B cells was associated with the activation of CIP/KIP family members of cdk inhibitors.
Tvrdík
D
D
Laboratory of Gene Expression, 1st Faculty of Medicine, Charles University, Albertov 4, Prague, Czech Republic.
Djaborkhel
R
R
Nagy
A
A
Eckschlager
T
T
Raska
I
I
Müller
J
J
D015153:Blotting, Western; D002455:Cell Division; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000737:chemistry / Q000378:metabolism*; D016213:Cyclins / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D016193:G1 Phase; D006801:Humans; D008223:Lymphoma / Q000378:metabolism*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases