Hasumi Hisashi, Baba Masaya, Hong Seung-Beom, Hasumi Yukiko, Huang Ying, Yao Masahiro, Valera Vladimir A, Linehan W Marston, Schmidt Laura S
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20894, United States.
Gene. 2008 May 31;415(1-2):60-7. doi: 10.1016/j.gene.2008.02.022. Epub 2008 Mar 4.
Birt-Hogg-Dube' syndrome characterized by increased risk for renal neoplasia is caused by germline mutations in the BHD/FLCN gene encoding a novel tumor suppressor protein, folliculin(FLCN), which interacts with FNIP1 and 5'-AMP-activated protein kinase(AMPK). Here we report the identification and characterization of a novel FNIP1 homolog FNIP2 that also interacts with FLCN and AMPK. C-terminally-deleted FLCN mutants, similar to those produced by naturally-occurring germline mutations in BHD patients, were unable to bind FNIP2. These data taken together with our previous results that demonstrated FNIP1 binding to the C-terminus of FLCN suggest that FLCN tumor suppressor function may be facilitated by interactions with both FNIP1 and FNIP2 through its C-terminus. Furthermore, we demonstrate that FNIP1 and FNIP2 are able to form homo- or heteromeric multimers suggesting that they may function independently or cooperatively with FLCN. Differential expression of FNIP1 and FNIP2 transcripts in some normal tissues may indicate tissue specificity for these homologs. Interestingly FNIP1 and FNIP2 were oppositely expressed in human clear cell renal cell carcinoma (RCC), and coordinately expressed in chromophobe RCC and oncocytoma, suggesting their differential function in different histologic variants of RCC.
Birt-Hogg-Dube综合征以肾肿瘤发生风险增加为特征，由编码一种新型肿瘤抑制蛋白卵泡抑素（FLCN）的BHD/FLCN基因的种系突变引起，该蛋白与FNIP1和5'-AMP激活蛋白激酶（AMPK）相互作用。在此，我们报告了一种新型FNIP1同源物FNIP2的鉴定和特征，它也与FLCN和AMPK相互作用。C末端缺失的FLCN突变体，类似于BHD患者自然发生的种系突变所产生的突变体，无法结合FNIP2。这些数据与我们之前证明FNIP1与FLCN的C末端结合的结果一起表明，FLCN的肿瘤抑制功能可能通过其C末端与FNIP1和FNIP2的相互作用而得到促进。此外，我们证明FNIP1和FNIP2能够形成同源或异源多聚体，表明它们可能与FLCN独立发挥作用或协同发挥作用。FNIP1和FNIP2转录本在一些正常组织中的差异表达可能表明这些同源物具有组织特异性。有趣的是，FNIP1和FNIP2在人透明细胞肾细胞癌（RCC）中呈相反表达，而在嫌色性RCC和嗜酸细胞瘤中呈协同表达，这表明它们在RCC的不同组织学变体中具有不同的功能。
