The role of the Birt-Hogg-Dubé protein in mTOR activation and renal tumorigenesis.
The role of the Birt-Hogg-Dubé protein in mTOR activation and renal tumorigenesis.
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DOI：
10.1038/onc.2009.14
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发表时间：
2009-04-02
期刊：
影响因子：
8
通讯作者：
Henske, E. P.
中科院分区：
文献类型：
--
作者：
Hartman, T. R.;Nicolas, E.;Klein-Szanto, A.;Al-Saleem, T.;Cash, T. P.;Simon, M. C.;Henske, E. P.
Birt-Hogg-Dubé综合征(BHD)是一种以皮肤肿瘤、囊性肺疾病和肾细胞癌为特征的肿瘤抑制基因紊乱。目前对BHD的分子发病机制知之甚少。BHD和结节性硬化症(TSC)的临床相似性表明，BHD和TSC蛋白可能在共同的途径中发挥作用。TSC蛋白抑制哺乳动物靶标雷帕霉素复合体1(TORC1)的活性，而在裂殖酵母中，Bhd和TSC1/TSC2在调节氨基酸动态平衡方面具有相反的作用。我们在这里报道，在哺乳动物细胞中，BHD的下调减少了核糖体蛋白S6的磷酸化，核糖体蛋白S6是TORC1活性的指标。为了确定BHD基因的产物毛囊蛋白是否调节体内的mTOR活性，我们产生了一只定向失活Bhd基因的小鼠。这些小鼠出现了自发的嗜酸细胞囊肿和肿瘤，这些肿瘤由类似于BHD患者肾细胞癌的细胞组成。囊和肿瘤的磷酸化S6水平较低。综上所述，这些数据表明，毛囊蛋白调节TORC1的活性，并提出了一种新的范式，即不适当的高水平和不适当的低水平的TORC1活性都可能与肾脏肿瘤的发生有关。
Birt-Hogg-Dubé (BHD) syndrome is a tumor suppressor gene disorder characterized by skin tumors, cystic lung disease, and renal cell carcinoma. Very little is known about the molecular pathogenesis of BHD. Clinical similarities between BHD and tuberous sclerosis complex (TSC) suggest that the BHD and TSC proteins may function within a common pathway. The TSC proteins inhibit the activity of the mammalian target of Rapamycin complex 1 (TORC1), and in Schizosaccharomyces pombe, Bhd and Tsc1/Tsc2 have opposing roles in the regulation of amino acid homeostasis. We report here that in mammalian cells, downregulation of BHD reduces the phosphorylation of ribosomal protein S6, an indicator of TORC1 activity. To determine whether folliculin, the product of the BHD gene, regulates mTOR activity in vivo, we generated a mouse with targeted inactivation of the Bhd gene. The mice developed spontaneous oncocytic cysts and tumors composed of cells that resemble the renal cell carcinomas in BHD patients. The cysts and tumors had low levels of phospho-S6. Taken together, these data indicate that folliculin regulates the activity of TORC1, and suggest a new paradigm in which both inappropriately high and inappropriately low levels of TORC1 activity can be associated with renal tumorigenesis.
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DOI：
10.1073/pnas.0409143102
发表时间：
2005-01-18
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.151033798
发表时间：
2001-07-17
影响因子：
11.1
作者：
Kobayashi, T;Minowa, O;Hino, O
通讯作者：
Hino, O
DOI：
10.1111/j.1349-7006.2001.tb02133.x
发表时间：
2001-11-01
期刊：
JAPANESE JOURNAL OF CANCER RESEARCH
影响因子：
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作者：
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通讯作者：
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