CDK6 blocks differentiation: coupling cell proliferation to the block to differentiation in leukemic cells.
Cell proliferation and differentiation are highly coordinated during normal development. Many tumor cells exhibit both uncontrolled proliferation and a block to terminal differentiation. To understand the mechanisms coordinating these two processes, we have investigated the relation between cyclin-dependent kinase (CDK) activities and the block to differentiation in murine erythroleukemia (MEL) cells. We found that CDK6 (but not CDK4) is rapidly downregulated as MEL cells are induced to re-enter erythroid differentiation and that maintenance of CDK6 (but not CDK4) activity by transfection blocks differentiation. Moreover, we found that PU.1, an Ets transcription factor that is oncogenic in erythroid cells and also can block their differentiation, controls the synthesis of CDK6 mRNA. These results suggest a mechanism for coupling proliferation and the block to differentiation in these leukemic cells through the action of an oncogenic transcription factor (PU.1) on a key cell cycle regulator (CDK6). Our findings suggest that studying the relative roles of CDK6 and CDK4 in other types of malignant cells will be important in designing approaches for cell cycle inhibition and differentiation therapy in cancer.
Matushansky
Igor
I
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Radparvar
Farshid
F
Skoultchi
Arthur I
AI
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002454:Cell Differentiation; D002455:Cell Division; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000378:metabolism / Q000502:physiology*; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015536:Down-Regulation; D007938:Leukemia / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D000099232:Proto-Oncogene Protein Spi-1
D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D003513:Cycloheximide; D004247:DNA; D004121:Dimethyl Sulfoxide; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse