Strasberg Rieber M, Rieber M
I.V.I.C., Tumor Cell Biology Laboratory, Caracas, Venezuela.
Biochem Biophys Res Commun. 1995 Nov 2;216(1):422-7. doi: 10.1006/bbrc.1995.2640.
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.
为了鉴定与黑色素瘤细胞增殖控制特异性相关的细胞周期蛋白，我们现在比较了据报道为血液系统恶性肿瘤标志物的细胞周期蛋白A与细胞周期蛋白D及其cdk4激酶伴侣的表达。所有这些蛋白均在增殖的B16黑色素瘤中表达。然而，诱导黑色素瘤终末分化的L-酪氨酸选择性降低了细胞周期蛋白D，而对cdk4或细胞周期蛋白A没有类似影响。将细胞暴露于酪氨酸磷酸酶抑制剂钒酸钠2小时，进一步降低了分化细胞中的细胞周期蛋白D，这表明酪氨酸磷酸化调节细胞周期蛋白D的周转。向饥饿细胞中添加血清也表明，酪氨酸并未阻断与血清刺激相关的细胞周期蛋白D的早期增加，但加速了其随后的减少。我们的数据表明，即使在携带突变或转录沉默的cdk4抑制剂肿瘤抑制基因p16ink4的细胞中，随着黑色素瘤终末分化而导致的细胞周期蛋白D减少也可能是一种生长停滞的替代模式。这些结果还意味着细胞周期蛋白D可能作为黑色素瘤治疗的靶点和预后标志物。
