Derivatives of Vitamins D2 and D3 Activate Three MAPK Pathways and Upregulate pRb Expression in Differentiating HL60 Cells
Derivatives of Vitamins D2 and D3 Activate Three MAPK Pathways and Upregulate pRb Expression in Differentiating HL60 Cells
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DOI：
10.4161/cc.1.6.269
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发表时间：
2002-11-01
期刊：
影响因子：
4.3
通讯作者：
Studzinski, George P.
中科院分区：
文献类型：
--
作者：
Ji, Yan;Kutner, Andrzej;Studzinski, George P.
人们已经合成了维生素D类似物，它们可以降低血钙活性，同时增加抗增殖和诱导分化的特性，这提高了人们对它们将用于治疗人类肿瘤疾病的期望。在本研究中，我们比较了三个这样的类似物，24 a，24 b-二高-1，25-二羟基维生素D-3（PRI-1890），24-烯-1，25-二羟基维生素D-2（PRI-1906）和（24 R）-1，24-二羟基维生素D-3（PRI-2191）诱导人早幼粒细胞白血病细胞HL 60中分化、G（1）期阻滞和相关分子事件的标志物（CD 14、CD 11b和MSE）。我们发现类似物诱导分化的效力与它们激活Erk、JNK和p38丝裂原活化蛋白激酶（MAPK）途径有关，并且抗增殖活性与视网膜母细胞瘤蛋白（pRb）的低磷酸化程度密切相关。有趣的是，低浓度的维生素D衍生物，这是不足以引起任何可检测到的变化，在细胞周期遍历，显着增加的水平，总pRb，这是高度磷酸化。这些结果表明pRb可能在单核细胞分化中有一个未知的作用，可能是通过增加细胞周期蛋白依赖性激酶的底物量来增加G（1）检查点的敏感性。
Analogs of vitamin D have been synthesized which have reduced calcemic activities yet increased anti-proliferative and differentiation-inducing properties, raising expectations that they will be useful for treatment of human neoplastic diseases. In the present study we compared the abilities of three such analogs, 24a, 24b-dihomo-1,25-dihydroxyvitamin D-3 (PRI-1890), 24-ene-1,25-dihydroxyvitamin D-2 (PRI-1906) and (24R)-1,24-dihydroxy-vitamin D-3 (PRI-2191) to induce markers (CD14, CD11b and MSE) of differentiation, G(1) phase block, and associated molecular events in human promyeloblastic leukemia cells HL60. We found that the potencies of the analogs to induce differentiation paralleled their activation of Erk, JNK and p38 mitogen-activated protein kinase (MAPK) pathways, and the anti-proliferative activity closely correlated with the extent of hypophosphorylation of retinoblastoma protein (pRb). Interestingly, low concentrations of derivatives of vitamin D, which were insufficient to induce any detectable changes in the cell cycle traverse, markedly increased the levels of total pRb, which was highly phosphorylated. These results suggest that pRb may have an unsuspected role in monocytic differentiation, perhaps to increase the sensitivity of the G(1) checkpoint, by increasing the amount of substrate for cyclin-dependent kinases.