MECHANISM OF TAXOL INDUCED APOPTOSIS

紫杉醇稳定微管，是最有效的药物之一 转移性乳腺癌和卵巢癌的治疗机制 紫杉醇通过何种途径诱导生长停滞和细胞毒性不佳 明白了。在研究紫杉醇与药物结合后的作用机制 对于微管，我们已经证明紫杉醇在一定的剂量和时间内诱导- 依赖方式，细胞周期蛋白抑制物p21在两种p53中的积聚 野生型和P53阴性细胞。在表达野生型p53的细胞中，这 紫杉醇处理也会诱导蛋白质，这种诱导是 主要通过增加蛋白质的稳定性来调节。重合 在这些作用下，紫杉醇治疗导致c-raf-1的激活。 蛋白水解酶和MAPK。C-raf-1的药理耗竭作用 苯醌阿霉素类药物可阻断紫杉醇诱导 野生型p53和细胞周期蛋白抑制剂p21以及紫杉醇诱导的 细胞毒性，暗示c-raf-1是紫杉醇作用的中介。英国皇家空军-L 已被证明与抗细胞凋亡剂形成了分子复合体 蛋白Bcl2。紫杉醇治疗后，这种复合体解离， 与Bc l-2的磷酸化一致。Bcl-2磷酸化有 与它的失活有关。由于药物耗竭， 我们的数据显示，c-raf-1还能阻断紫杉醇后的bcl2磷酸化。 C-raf-1参与失活bc-2蛋白的研究 在紫杉醇治疗后。我们的发现表明了一种新的机制 紫杉醇诱导的细胞毒性，涉及不同的亚细胞池的c- RAF-L，并涉及Bcl2和细胞周期蛋白抑制因子p21。

Taxol stabilizes microtubules and is one of the most effective drugs for the treatment of metastatic breast and ovarian cancer, yet the mechanism by which taxol induces growth arrest and cytotoxicity is not well understood. In studying taxol's mechanism of action after the drug binds to microtubules, we have shown that taxol induces, in a dose-and time- dependent fashion, accumulation of the cyclin inhibitor p21 in both p53 wild type and p53-null cells. In cells expressing wild type p53, this protein is also induced by taxol treatment, and this induction is mediated primarily by increased stability of the protein. Coincident with these effects, taxol treatment results in activation of c-raf-1 kinase and MAP kinase. Pharmacologic depletion of c-raf-1 with benzoquinone ansamycins abrogates both the ability of taxol to induce both wild type p53 and the cyclin inhibitor p21, as well as taxol-induced cytotoxicity, implicating c-raf-1 as a mediator of taxol action. Raf-l has been shown to form a molecular complex with the anti-apoptotic protein Bcl-2. Following taxol treatment, this complex dissociates, coincident with the phosphorylation of Bcl-2. Bcl-2 phosphorylation has been associated with its inactivation. Since pharmacologic depletion of c-raf-1 also blocks Bcl-2 phosphorylation following taxol, our data implicate c-raf-1 as the kinase responsible for inactivating Bcl-2 following taxol treatment. Our findings suggest a novel mechanism of taxol-induced cytotoxicity, involving a distinct subcellular pool of c- raf-l, and involving Bcl-2 and the cyclin inhibitor p2l.