Retinoic acid modulates a bimodal effect on cell cycle progression in human adult T-cell leukemia cells.
Retinoids, the analogues of vitamin A, have a broad range of effects on different cell types. One biologically active form of vitamin A is all-trans-retinoic acid (ATRA), which binds to retinoic acid receptors, as does its intracellular metabolite, 9-cis-RA. Earlier studies have documented G1 cell cycle arrest and the induction of apoptosis in human adult T-cell leukemia cells after ATRA treatment. Previous work exploring the growth-inhibitory activity of ATRA in human malignancies has implicated several mechanisms that can arrest cells in the G1 phase of the cell cycle, including activation of p21Waf1 and inhibition of cyclin D1 expression. Therefore, we decided to examine the effects of ATRA exposure on G1 cell cycle components in human adult T-cell leukemia cells. Our data demonstrate a correlation between cyclin/cyclin-dependent kinase activity and subunit complex formation with duration of drug exposure. We also observed an increase in p53 protein levels that were not associated with an increase in p21Waf1 levels. Furthermore, we observed a differential effect on cell cycle progression that was temporally related to length of ATRA exposure. These observations, consistent with a bimodal effect of ATRA on cell cycle progression, may have important implications for the clinical application of ATRA.
Dierov
J
J
Center for NeuroVirology and NeuroOncology, MCP Hahnemann School of Medicine, Philadelphia, Pennsylvania 19102, USA.
Sawaya
B E
BE
Prosniak
M
M
Gartenhaus
R B
RB
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D015368:Human T-lymphotropic virus 1; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D013601:T-Lymphocytes / Q000201:enzymology / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D014212:Tretinoin; D017346:Protein Serine-Threonine Kinases; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases