Beclin 1 contains a leucine-rich nuclear export signal that is required for its autophagy and tumor suppressor function.
Beclin 1 contains a leucine-rich nuclear export signal that is required for its autophagy and tumor suppressor function.
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DOI：
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发表时间：
2001-04
期刊：
影响因子：
11.2
通讯作者：
X. Liang;Jie Yu;K. Brown;B. Levine
中科院分区：
文献类型：
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作者：
X. Liang;Jie Yu;K. Brown;B. Levine
Beclin 1编码具有自噬和肿瘤抑制功能的Bcl-2相互作用卷曲螺旋蛋白，并且在40-75%的散发性人类乳腺癌和卵巢癌中单等位基因缺失。Beclin 1含有一个富含亮氨酸的核输出信号基序，提高了其自噬和/或肿瘤抑制功能可能需要调节的CRM 1依赖性核质转运的可能性。在这项研究中，我们发现野生型Beclin 1与COS 7猴肾和MCF 7人乳腺癌细胞的胞浆内细胞器和细胞核共定位。用链霉素B或Beclin 1的核输出信号基序的突变抑制CRM 1依赖的核输出导致主要的核定位。与野生型Beclin 1不同，Beclin 1的核输出突变体不能促进营养缺乏诱导的自噬，并且不能抑制MCF 7细胞的体外克隆形成性和体内致瘤性。因此，beclin 1具有一个对来普霉素B敏感的富含亮氨酸的核输出信号，这是其自噬和肿瘤抑制功能所必需的。这些发现表明，CRM 1核输出途径可能是重要的自噬生长控制的功能调节。
Beclin 1 encodes a Bcl-2-interacting coiled-coil protein with autophagy and tumor suppressor function and is monoallelically deleted in 40-75% of sporadic human breast and ovarian cancers. Beclin 1 contains a leucine-rich nuclear export signal motif raising the possibility that its autophagy and/or tumor suppressor function may require regulated, CRM1-dependent, nucleocytoplasmic transport. In this study, we show that wild-type Beclin 1 colocalizes with both intracytoplasmic organelles and nuclei in COS7 monkey kidney and MCF7 human breast carcinoma cells. Inhibition of CRM1-dependent nuclear export with leptomycin B or mutation of the nuclear export signal motif of Beclin 1 results in predominantly nuclear localization. Unlike wild-type Beclin 1, the nuclear export mutant of Beclin 1 fails to promote nutrient deprivation-induced autophagy and fails to inhibit in vitro clonigenicity and in vivo tumorigenicity of MCF7 cells. Thus, beclin 1 has a leptomycin B-sensitive leucine-rich nuclear export signal that is required for its autophagy and tumor suppressor function. These findings suggest that the CRM1 nuclear export pathway may be important in the functional regulation of autophagic growth control.