Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-beta in cells lacking the CDK inhibitor p15.
The activity of the cyclin-dependent kinases (CDKs) that control cell growth and division can be negatively regulated by tyrosine phosphorylation or by the binding of various CDK inhibitors. Whereas regulation by tyrosine phosphorylation is well documented in CDKs that function during mitosis, little is known about its role in the regulation of CDKs that act in the G1 phase of the cell cycle. In contrast, much evidence has accumulated on the regulation of G1 CDKs by CDK inhibitors. The cytokine TGF-beta inhibits growth by causing cell-cycle arrest as a result of increasing the concentration of the Cdk4/6 inhibitor p15(INK4B/MTS2) (refs 3, 4). Here we report that TGF-beta can also cause the inhibition of Cdk4 and Cdk6 by increasing their level of tyrosine phosphorylation. Tyrosine phosphorylation and inactivation of Cdk4/6 in a human mammary epithelial cell line are shown to result from the ability of TGF-beta to repress expression of the CDK tyrosine phosphatase Cdc25A. Repression of Cdc25A and induction of p15 are independent effects mediating the inhibition of Cdk4/6 by TFG-beta.
Iavarone
A
A
Cell Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Massagué
J
J
D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D016296:Mutagenesis; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D010749:Phosphoprotein Phosphatases; D020687:cdc25 Phosphatases