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Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105

Abstract

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 subchromosomal 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 define a novel ubiquitin–proteasome pathway that targets TSSC5 in mammalian cells.

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Acknowledgements

This research is supported by a fellowship from the Breast Cancer Research Program of the US Department of Defense to HY Yamada (DAMD17-02-1-0532), and by a grant from the National Institute of General Medical Science (RO1-GM50412) to GJ Gorbsky. We thank our laboratory members for support, Dr Takumi Kamura (Kyushu University, Japan) for reagents for ubiquitylation assays and Dr Scott Plafker (University of Oklahoma Health Sciences Center) for suggestions.

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Correspondence to H Y Yamada.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Yamada, H., Gorbsky, G. Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105. Oncogene 25, 1330–1339 (2006). https://doi.org/10.1038/sj.onc.1209167

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