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Manipulating the onset of cell cycle withdrawal in differentiated erythroid cells with cyclin-dependent kinases and inhibitors.
- Source :
-
Blood [Blood] 2000 Oct 15; Vol. 96 (8), pp. 2755-64. - Publication Year :
- 2000
-
Abstract
- Terminal differentiation of erythroid cells results in terminal cell divisions followed by irreversible cell cycle withdrawal of hemoglobinized cells. The mechanisms leading to cell cycle withdrawal were assessed in stable transfectants of murine erythroleukemia cells, in which the activities of cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs) could be tightly regulated during differentiation. Cell cycle withdrawal of differentiating cells is mediated by induction of several CDKIs, thereby leading to inhibition of CDK2 and CDK4. Manipulation of CDK activity in differentiating cells demonstrates that the onset of cell cycle withdrawal can be either greatly accelerated or greatly delayed without affecting hemoglobin levels. Extending the proliferation of differentiating cells requires the synergistic action of CDK2 and CDK4. Importantly, CDK6 cannot substitute for CDK4 in this role, which demonstrates that the 2 cyclin D-dependent kinases are functionally different. The results show that differentiating hemoglobinized cells can be made to proliferate far beyond their normal capacity to divide. (Blood. 2000;96:2755-2764)
- Subjects :
- Acetamides pharmacology
Animals
Cell Differentiation drug effects
Cell Division
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Cyclin-Dependent Kinases antagonists & inhibitors
Cyclin-Dependent Kinases genetics
Enzyme Induction
Erythroid Precursor Cells cytology
Erythroid Precursor Cells enzymology
Gene Expression Regulation, Leukemic
Genetic Complementation Test
Hemoglobins biosynthesis
Humans
Leukemia, Erythroblastic, Acute pathology
Mice
Neoplasm Proteins antagonists & inhibitors
Neoplasm Proteins physiology
Protein Serine-Threonine Kinases antagonists & inhibitors
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases physiology
Recombinant Fusion Proteins physiology
Transfection
CDC2-CDC28 Kinases
Cell Cycle drug effects
Cyclin-Dependent Kinases physiology
Enzyme Inhibitors pharmacology
Erythroid Precursor Cells drug effects
Proto-Oncogene Proteins
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 96
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 11023509