Reference Report

Reference
Citation	Gemmill, R.M., Lee, J.P., Chamovitz, D.A., Segal, D., Hooper, J.E., Drabkin, H.A. (2005). Growth suppression induced by the TRC8 hereditary kidney cancer gene is dependent upon JAB1/CSN5. Oncogene 24(21): 3503--3511. (Export to RIS)
FlyBase ID	FBrf0206286
Publication Type	Research paper
PubMed ID	15735686
PubMed Abstract	TRC8 encodes an E3-ubiquitin ligase disrupted in a family with hereditary renal cell carcinoma (RCC). We previously reported that Drosophila Trc8 (DTrc8) overexpression inhibits growth and that human and fly proteins interact with with the COP9 signalosome (CSN) subunit JAB1/CSN5. However, further mechanistic evidence linking DTrc8 growth suppression to CSN5 was lacking. Here, we show that haploinsufficiency of CSN5, or a T100I point mutation (CSN5(3)), relieved growth suppression by DTrc8, whereas CSN5(1) (E160V) and CSN5(2) (G147D) mutations had no effect. The strength of yeast two-hybrid interactions between DTrc8 and CSN5 were in complete agreement with the observed phenotypes. DTrc8 overexpression resulted in elevated levels of CSN5 and CSN7, but had no effect on NEDD8-modified Cul-1. In contrast to CSN5, heterozygosity for CSN4null had no effect on the DTrc8 phenotype. We also looked for genetic interactions between DTrc8 and other MPN domain proteins in the CSN and 26S proteasome lid. CSN6 haploinsufficiency restored growth, whereas reduction of proteasome subunits RPN8 or RPN11 had no effect. DTrc8 expression increased the level of digitonin-extractable CSN complex, consistent with elevated levels of CSN5 and 7. Our genetic results confirm that DTrc8-induced growth suppression is CSN5 (and CSN6) dependent. While there was no obvious influence on CSN deneddylation activity, the increase in CSN subunits and holocomplex suggests that TRC8 modulates signalosome levels or compartmentalization.
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Language of Publication	English
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Publication Type	Journal
Abbreviation	Oncogene
Title	Oncogene
Publication Year	1987-
ISBN/ISSN	0950-9232
Data from Reference
Aberrations (1)
	Df(3R)hh
Alleles (11)
	CSN4^null CSN5^null CSN5^quo-1 CSN5^quo-2 CSN5^quo-3 Rpn8^k08003 Rpn11^BG01694 Scer\GAL4^Act.PU Scer\GAL4^Bx-MS1096 Scer\GAL4^en.PU Trc8^{Scer\UAS.T:Hsap\MYC}
Constructs (3)
	P{Act-GAL4.U} P{en-GAL4.U} P{UAS-Trc8.MYC}
Genes (9)
	CSN4 CSN5 CSN6 CSN7 lin19 Rpn8 Rpn11 Scer\GAL4 Trc8
Insertions (3)
	P{GawB}Bx^MS1096 P{GT1}Rpn11^BG01694 P{lacW}Rpn8^k08003
Natural transposons (1)
	P-element