Suppression of cyclin D1 but not cdk4 or cyclin A with induction of melanoma terminal differentiation.
To identify cyclins specifically associated with control of melanoma cell proliferation, we now compared expression of cyclin A, reported to be a marker for hematological malignancies, with that of cyclin D and its cdk4 kinase partner. All these proteins were expressed in proliferating B16 melanoma. However, L-tyrosine which induces melanoma terminal differentiation, selectively decreased cyclin D with no comparable effect on cdk4 or cyclin A. A 2-hour exposure of the cells to the tyrosine phosphatase inhibitor, sodium vanadate, further decreased cyclin D from differentiated cells, suggesting that tyrosine phosphorylation regulates cyclin D turnover. Addition of serum to starved cells also revealed that tyrosine did not block the early cyclin D increase associated with serum stimulation, but accelerated its subsequent loss. Our data suggest that cyclin D decrease with melanoma terminal differentiation could be an alternative mode of growth arrest even in cells harbouring a mutant or transcriptionally silent cdk4 inhibitor tumor suppressor p16ink4 gene. These results also imply that cyclin D may be useful as a target and as a prognostic marker in melanoma therapy.
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis*; D016213:Cyclins / Q000096:biosynthesis*; D016193:G1 Phase; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015513:Oncogene Proteins / Q000096:biosynthesis*; D011518:Proto-Oncogene Proteins; D016196:S Phase; D014443:Tyrosine / Q000494:pharmacology*; D014638:Vanadates / Q000494:pharmacology
D014408:Biomarkers, Tumor; D016213:Cyclins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; D014638:Vanadates; D014443:Tyrosine; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases