Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105.
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.
Yamada
H Y
HY
Oklahoma Medical Research Foundation (OMRF), Molecular, Cell and Developmental Biology Research Program, Oklahoma City, OK 73104, USA. Hiroshi-yamada@omrf.ouhsc.edu
Gorbsky
G J
GJ
D001506:Beckwith-Wiedemann Syndrome / Q000150:complications / Q000235:genetics; D002453:Cell Cycle; D002880:Chromosomes, Human, Pair 11; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D018392:Genomic Imprinting; D006367:HeLa Cells; D018197:Hepatoblastoma / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis* / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D009396:Wilms Tumor / Q000235:genetics; D016335:Zinc Fingers
D027701:Organic Cation Transport Proteins; C111653:SLC22A18 protein, human; D025801:Ubiquitin; C489963:UBE2E1 protein, human; D044763:Ubiquitin-Conjugating Enzymes; C108062:TTC3 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex