Sporadic renal angiomyolipoma in a patient with Birt-Hogg-Dubé: chaperones in pathogenesis.
Sporadic renal angiomyolipoma in a patient with Birt-Hogg-Dubé: chaperones in pathogenesis.
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DOI：
10.18632/oncotarget.25164
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发表时间：
2018-04-24
期刊：
影响因子：
--
通讯作者：
Bratslavsky G
中科院分区：
文献类型：
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作者：
Sager RA;Woodford MR;Shapiro O;Mollapour M;Bratslavsky G
Birt-Hogg-Dubé（BHD）是一种常染色体显性遗传综合征，由FLCN基因的种系突变引起，使患者易于发生肾肿瘤。肾血管平滑肌脂肪瘤（AML）不是与BHD相关的肾肿瘤亚型。然而，AML是由TSC 1或TSC 2肿瘤抑制基因突变引起的多发性硬化综合征（TSC）的常见表型表现。先前BHD患者中肾AML的病例报告推测这两种综合征的分子和临床重叠是由于所描述的mTOR通路中基因产物的参与。我们最近的工作提供了一个新的分子之间的联系，这两个综合征通过确定FLCN和Tsc 2的客户端的分子伴侣Hsp 90。FNIP 1/2和Tsc 1作为新的Hsp 90共伴侣蛋白对FLCN和Tsc 2的稳定性具有重要意义。在这里，我们提出了一个散发性急性髓细胞白血病的结果，体细胞Tsc 1/2的损失与BHD患者。我们进一步证明了FNIP 1和Tsc 1能够在突变的FLCN肿瘤抑制因子的陪伴中相互补偿。我们的研究结果表明BHD和TSC途径之间的相互联系和补偿机制。
Birt-Hogg-Dubé (BHD) is an autosomal dominant genetic syndrome caused by germline mutations in the FLCN gene that predisposes patients to develop renal tumors. Renal angiomyolipoma (AML) is not a renal tumor sub-type associated with BHD. AML is, however, a common phenotypic manifestation of Tuberous Sclerosis Complex (TSC) syndrome caused by mutations in either the TSC1 or TSC2 tumor suppressor genes. Previous case reports of renal AML in patients with BHD have speculated on the molecular and clinical overlap of these two syndromes as a result of described involvement of the gene products in the mTOR pathway. Our recent work provided a new molecular link between these two syndromes by identifying FLCN and Tsc2 as clients of the molecular chaperone Hsp90. Folliculin interacting proteins FNIP1/2 and Tsc1 are important for FLCN and Tsc2 stability as new Hsp90 co-chaperones. Here we present a case of sporadic AML as a result of somatic Tsc1/2 loss in a patient with BHD. We further demonstrate that FNIP1 and Tsc1 are capable of compensating for each other in the chaperoning of mutated FLCN tumor suppressor. Our findings demonstrate interconnectivity and compensatory mechanisms between the BHD and TSC pathways.