Haldar S, Basu A, Croce C M
Department of Pharmacology, Ireland Cancer Center, Case Western Reserve University, Cleveland, Ohio 44109, USA.
Cancer Res. 1998 Apr 15;58(8):1609-15.
Taxoids and other microtubule-damaging drugs are known to induce Bcl2 phosphorylation at the G2-M phase of the cell cycle, with concomitant apoptosis in malignant cells derived from a variety of human malignancies, including leukemia, lymphoma, and breast and prostate cancer. We have investigated the ability of another antineoplastic drug, dolastatin 10, in inducing Bcl2 phosphorylation and apoptosis. We also investigated the effects of a phosphatase inhibitor okadaic acid in the regulation of Bcl2 phosphorylation, cell cycle arrest, and programmed cell death. Moreover, site-directed mutagenesis studies were performed to determine the specific serine residue(s) responsible for drug-induced Bcl2 phosphorylation. Our results indicate that these antimicrotubule agents or okadaic acid can induce posttranslational modification (phosphorylation) of Bcl2 protein at multiple serine residues. Interestingly, mutation of a serine residue at position 70 to alanine can significantly decrease drug-induced posttranslational modification (phosphorylation) of Bcl2 protein. Apparently, Ser70 seems to be a critical site for drug-induced posttranslational modification (phosphorylation) of the Bcl2 protein.
紫杉烷类和其他破坏微管的药物已知可在细胞周期的G2-M期诱导Bcl2磷酸化，并伴随源自多种人类恶性肿瘤（包括白血病、淋巴瘤以及乳腺癌和前列腺癌）的恶性细胞发生凋亡。我们研究了另一种抗肿瘤药物多拉司他汀10诱导Bcl2磷酸化和凋亡的能力。我们还研究了磷酸酶抑制剂冈田酸对Bcl2磷酸化、细胞周期阻滞和程序性细胞死亡的调节作用。此外，进行了定点诱变研究以确定负责药物诱导的Bcl2磷酸化的特定丝氨酸残基。我们的结果表明，这些抗微管药物或冈田酸可在多个丝氨酸残基处诱导Bcl2蛋白的翻译后修饰（磷酸化）。有趣的是，将第70位的丝氨酸残基突变为丙氨酸可显著降低药物诱导的Bcl2蛋白翻译后修饰（磷酸化）。显然，Ser70似乎是药物诱导的Bcl2蛋白翻译后修饰（磷酸化）的关键位点。
