Ochel H J, Schulte T W, Nguyen P, Trepel J, Neckers L
Medicine Branch, National Cancer Institute, Rockville, Maryland, 20850, USA.
Mol Genet Metab. 1999 Jan;66(1):24-30. doi: 10.1006/mgme.1998.2774.
FAK is a nonreceptor tyrosine kinase involved in adhesion-mediated signal transduction whose level of expression is related to the invasiveness of malignant tumors. In seeking strategies to downregulate FAK, we treated various cell lines in vitro with the benzoquinone ansamycin geldanamycin (GA) which was previously described as a tyrosine kinase inhibitor, but recently has been shown to exert its effects by interfering with the chaperone function of members of the hsp90 family of heat-shock proteins. We evaluated the effects of benzoquinone ansamycins on FAK steady-state protein level and FAK half-life in breast and prostate carcinoma, Ewing's sarcoma, and 3T3 fibroblasts. Our data demonstrate that GA stimulates the proteolytic degradation of FAK in all cell lines examined and markedly reduces the half-life of newly synthesized FAK protein without significantly altering the level of FAK mRNA. These data demonstrate FAK to be another tyrosine kinase sensitive to the destabilizing effects of benzoquinone ansamycins and further show that small molecule-mediated pharmacologic modulation of FAK protein level is a feasible approach to the interdiction of FAK function.
黏着斑激酶（FAK）是一种参与黏附介导信号转导的非受体酪氨酸激酶，其表达水平与恶性肿瘤的侵袭性有关。在寻找下调FAK的策略时，我们用苯醌安莎霉素格尔德霉素（GA）体外处理了各种细胞系，GA先前被描述为一种酪氨酸激酶抑制剂，但最近已证明它是通过干扰热休克蛋白hsp90家族成员的伴侣功能来发挥作用的。我们评估了苯醌安莎霉素对乳腺癌、前列腺癌、尤因肉瘤和3T3成纤维细胞中FAK稳态蛋白水平和FAK半衰期的影响。我们的数据表明，GA在所有检测的细胞系中均刺激FAK的蛋白水解降解，并显著缩短新合成的FAK蛋白的半衰期，而不会显著改变FAK mRNA的水平。这些数据表明FAK是另一种对苯醌安莎霉素的去稳定作用敏感的酪氨酸激酶，并进一步表明小分子介导的FAK蛋白水平的药理调节是阻断FAK功能的一种可行方法。
