Dissociation of Bax from a Bcl-2/Bax heterodimer triggered by phosphorylation of serine 70 of Bcl-2
Dissociation of Bax from a Bcl-2/Bax heterodimer triggered by phosphorylation of serine 70 of Bcl-2
复制标题
DOI：
10.1093/oxfordjournals.jbchem.a003044
复制
发表时间：
2001-12-01
影响因子：
2.7
通讯作者：
Shibasaki, F
中科院分区：
文献类型：
--
作者：
Shitashige, M;Toi, M;Shibasaki, F
在表达 Bcl-2 的肿瘤细胞和 BHK 细胞中，通过紫杉醇处理，Bcl-2 环区的丝氨酸 70 被特异性磷酸化。 Bcl-2 (pS70-Bcl-2) 丝氨酸 70 的磷酸化在紫杉醇治疗后 24 至 48 小时达到峰值，并加速细胞凋亡。在放线菌素 D 或放线菌酮存在下，磷酸化会被有效抑制，从而使细胞活力恢复到与不表达 Bcl-2 的对照细胞相同的水平。这些结果表明紫杉醇诱导的激酶和/或其激活剂是从头合成的，并且通过磷酸化Bcl-2在紫杉醇诱导的细胞凋亡中发挥重要作用。在使用针对 pS70-Bcl-2 的磷酸化特异性抗体进行的结合测定中，丝氨酸 70 磷酸化 70 的诱导导致 Bcl-2 与促凋亡伙伴 Bax 的结合能力丧失，并诱导随后的细胞死亡。当将 pS70-Bcl-2 抗体添加到人乳腺癌组织中时，甚至在用抗癌药物治疗之前也检测到丝氨酸 70 磷酸化。 F-Lu-ther 对乳腺癌的研究表明，83% pS70-Bcl-2 高表达的肿瘤对紫杉醇或多西他赛治疗有反应，而 57% 低表达的肿瘤则无反应。这些发现表明 pS70-Bcl-2 可能是乳腺癌预后和紫杉醇治疗敏感性的预测因素。
Serine 70 in the loop region of Bcl-2 is specifically phosphorylated by paclitaxel-treatment in tumor cells and BHK cells expressing Bcl-2. The phosphorylation of serine 70 of Bcl-2 (pS70-Bcl-2) peaks 24 to 48 h after paclitaxel treatment and accelerates apoptosis. Phosphorylation is effectively inhibited in the presence of actinomycin D or cycloheximide, which restore cell viability to the same level as control cells not expressing Bcl-2. These results indicate that paclitaxel-induced kinase(s) and/or its activator(s) are synthesized de novo and play an important role in paclitaxel-induced apoptosis by phosphorylating Bcl-2. In binding assays using the phosphorylation-specific antibody against pS70-Bcl-2, the induction of serine 70 phosphorylation 70 results in a loss of the binding ability of Bcl-2 to Bax, a pro-apoptotic partner, and induces subsequent cell death. When the pS70-Bcl-2 antibody was added to human breast cancer tissue, serine 70 phosphorylation was also detected, even prior to treatment with anticancer agents. F-Lu-ther study of breast cancers revealed 83% of tumors with high pS70-Bcl-2 expression responded to paclitaxel or docetaxel treatment, whereas 57% of those with low expression not respond. These findings suggest that pS70-Bcl-2 might be a predictive factor for prognosis and sensitivity to paclitaxel treatment for breast cancer.