Inhibition of Hsp90 function by ansamycins causes retinoblastoma gene product-dependent G1 arrest.
Inhibition of Hsp90 function by ansamycins causes retinoblastoma gene product-dependent G1 arrest.
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发表时间：
2000-07
期刊：
影响因子：
11.2
通讯作者：
Mary Srethapakdi;Franklin Liu;Ranjana Tavorath;Neal Rosen
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作者：
Mary Srethapakdi;Franklin Liu;Ranjana Tavorath;Neal Rosen
安莎霉素抗生素、除草霉素 A (HA) 和格尔德霉素 (GM) 与热休克蛋白 90 (Hsp90) 的保守口袋结合，并改变该伴侣蛋白的功能。该口袋的占据导致信号分子子集的降解。这些包括已知与 Hsp90 相关的蛋白质，例如类固醇受体和 Raf，以及某些跨膜酪氨酸激酶，例如 ErbB 受体家族。在多种肿瘤细胞系中，HA 治疗可通过诱导 G1 期停滞来有效抑制细胞增殖。这种停滞伴随着视网膜母细胞瘤基因产物 (RB) 的低磷酸化以及细胞周期蛋白 D 和 E 相关激酶活性的快速下调。发现激酶活性的抑制是由于细胞周期蛋白 D1、D3 和 E 以及相关的细胞周期蛋白依赖性激酶、细胞周期蛋白依赖性激酶 4 和细胞周期蛋白依赖性激酶 6 的表达丧失所致。此外，HA 处理还导致 p27(Kip1) 蛋白的晚期诱导。 cyclin D 的丢失先于 HA 的其他影响，表明它可能是 G1 期停滞的主要原因。为了确定HA的作用是否是通过选择性抑制细胞周期蛋白D-RB途径介导的，将HA添加到缺乏功能性RB的肿瘤细胞系中。 HA 处理 Rb 阴性肿瘤细胞系未能引起 G1 期停滞。此外，在与诺考达唑同步释放后，Rb阴性但不是Rb阳性细胞系能够在HA存在下从G1期进展到S期。总之，这些发现表明 HA 诱导 G1 期停滞是由于细胞周期蛋白 D 表达及其相关激酶活性下调所致。此外，这些发现表明 Hsp90 选择性调节 RB 上游的信号通路。
The ansamycin antibiotics, herbimycin A (HA) and geldanamycin (GM), bind to a conserved pocket in heat shock protein 90 (Hsp90) and alter the function of this chaperone protein. Occupancy of this pocket results in the degradation of a subset of signaling molecules. These include proteins known to associate with Hsp90, e.g., the steroid receptors and Raf, as well as certain transmembrane tyrosine kinases, such as the ErbB receptor family. In a variety of tumor cell lines, treatment with HA potently inhibited cellular proliferation by inducing G1 arrest. This arrest was accompanied by hypophosphorylation of the retinoblastoma gene product (RB) and rapid down-regulation of cyclin D- and E-associated kinase activities. Inhibition of kinase activity was found to result from loss in expression of cyclins D1, D3, and E, as well as the associated cyclin-dependent kinases, cyclin-dependent kinase 4 and cyclin-dependent kinase 6. In addition, HA treatment also caused a late induction of p27(Kip1) protein. The loss of cyclin D preceded the other effects of HA, suggesting that it might be the primary cause of G1 arrest. To determine whether the effects of HA are mediated by selective inhibition of the cyclin D-RB pathway, HA was added to tumor cell lines lacking functional RB. HA treatment of Rb-negative tumor cell lines failed to elicit a G1 arrest. In addition, after release from synchronization with nocodazole, Rb-negative but not Rb-positive cell lines were able to progress through G1 into S phase in the presence of HA. Together, these findings suggest that induction of G1 arrest by HA results from down-regulation of cyclin D expression and its associated kinase activity. Furthermore, these findings imply that Hsp90 selectively regulates signaling pathways upstream of RB.