Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105
Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105
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DOI：
10.1038/sj.onc.1209167
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发表时间：
2006-03-02
期刊：
影响因子：
8
通讯作者：
Gorbsky, GJ
中科院分区：
文献类型：
--
作者：
Yamada, HY;Gorbsky, GJ
人类染色体11p15.5区域与Beckwith-Wiedemann综合征相关，该综合征与Wilms肿瘤、横纹肌肉瘤和肝母细胞瘤的易感性相关。TSSC 5（肿瘤抑制亚染色体可转移片段cDNA;也称为ORCTL 2/IMPT 1/BWR 1A/SLC 22 A1 L）位于该区域。TSSC 5和该区域其他基因的表达通过父系印记进行调节。在某些肿瘤中已经发现TSSC 5的突变和/或表达降低。TSSC 5编码一种具有10个跨膜结构域的外排转运蛋白样蛋白，其调控可能影响药物敏感性、细胞代谢和生长。在这里，我们提出的证据表明，RING 105，一种新的保守的环指蛋白与PA（蛋白酶相关）域和PEST序列，是一种泛素连接酶TSSC 5，可以在音乐会上与泛素结合酶UbcH 6。TSSC 5上的多聚泛素靶位点被定位到第6亲水环中的区域。HeLa细胞中RING 105的异位表达引起G1期细胞的积累，这在表达RING 105的形式中没有观察到，其中RING指内的残基被突变以抑制其连接酶活性。UbcH 6-RING 105可能是一种新的转基因植物。新的泛素-蛋白酶体途径，靶向哺乳动物细胞中的TSSC 5。
The region of human chromosome 11p15.5 is linked with Beckwith-Wiedemann syndrome that is associated with susceptibility to Wilms' tumor, rhabdomyosarcoma and hepatoblastoma. TSSC5 (tumor-suppressing subchromo-somal transferable fragment cDNA; also known as ORCTL2/IMPT1/BWR1A/SLC22A1L) is located in the region. The expression of TSSC5 and other genes in the region is regulated through paternal imprinting. Mutations and/or reduced expression of TSSC5 have been found in certain tumors. TSSC5 encodes an efflux transporter-like protein with 10 transmembrane domains, whose regulation may affect drug sensitivity, cellular metabolism and growth. Here, we present evidences indicating that RING105, a novel conserved RING-finger protein with a PA (protease-associated) domain and a PEST sequence, is a ubiquitin ligase for TSSC5 that can function in concert with the ubiquitin-conjugating enzyme UbcH6. The polyubiquitin target site on TSSC5 was mapped to a region in the 6th hydrophilic loop. Ectopic expression of RING105 in HeLa cells caused an accumulation of cells during G1 that was not observed with the expression of a form of RING105 in which a residue within the RING finger was mutated to inactivate its ligase activity. UbcH6-RING105 may de. ne a novel ubiquitin-proteasome pathway that targets TSSC5 in mammalian cells.