The benzoquinone ansamycin geldanamycin stimulates proteolytic degradation of focal adhesion kinase.
The benzoquinone ansamycin geldanamycin stimulates proteolytic degradation of focal adhesion kinase.
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DOI：
10.1006/mgme.1998.2774
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发表时间：
1999
影响因子：
3.8
通讯作者：
Hans-Joachim Ochel;Theodor W. Schulte;P. Nguyen;Jane B. Trepel;Len Neckers
中科院分区：
文献类型：
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作者：
Hans-Joachim Ochel;Theodor W. Schulte;P. Nguyen;Jane B. Trepel;Len Neckers
FAK是一种非受体酪氨酸激酶，参与黏附介导的信号转导，其表达水平与恶性肿瘤的侵袭性有关。为了寻求下调FAK的策略，我们在体外用苯醌阿萨霉素(GA)处理各种细胞系，GA以前被描述为酪氨酸激酶抑制剂，但最近被证明通过干扰HSP90家族成员的伴侣功能发挥其作用。我们评价了苯醌阿萨霉素对乳腺癌、前列腺癌、尤文氏肉瘤和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刺激所有细胞系中FAK的蛋白降解，并显著缩短新合成的FAK蛋白的半衰期，而不显著改变FAK mRNA的水平。这些数据表明，FAK是另一种对苯醌阿霉素类的不稳定作用敏感的酪氨酸激酶，并进一步表明小分子介导的药物调节FAK蛋白水平是阻断FAK功能的一种可行途径。
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.