The hereditary renal cell carcinoma 3;8 translocation fuses
 FHIT
 to a
 patched-
 related gene,
 TRC8

Gemmill, Robert M.; West, James; Boldog, Ferenc; Tanaka, Naotake; Robinson, Linda J.; Smith, Jeremy C.; Li, Frederick; Drabkin, Harry A.

doi:10.1073/pnas.95.16.9572

Cited by 142 publications

(123 citation statements)

References 48 publications

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“…Similar ®ndings were obtained using anti-HA antibodies or an a nity puri®ed polyclonal rabbit antiserum speci®c for hTRC8 (not shown). However, we were unable to detect endogenous TRC8 proteins by immuno¯uores-cence or Western blots despite ubiquitous mRNA in human (Gemmill et al, 1998) and Drosophila. Using a heat-shock inducible myc-tagged DTrc8 transgene in Drosophila embryos, DTrc8 was observed to disappear from Western blots after 15 min of recovery (not shown).…”

Section: Introductionmentioning

confidence: 93%

“…In addition, some t(3;8) carriers developed non-medullary thyroid cancer (Li et al, 1993), not a recognized feature of the VHL syndrome ). The t(3;8) breakpoint generates a fusion transcript involving the 5' untranslated portion of FHIT and the coding region of a novel gene, TRC8 (Gemmill et al, 1998). TRC8 encodes a multi-membrane spanning protein with partial similarity to the Hedgehog receptor, Patched (Hahn et al, 1996;Johnson et al, 1996;Gailani et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway

et al. 2002

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VHL is part of an SCF related E3-ubiquitin ligase complex with`gatekeeper' function in renal carcinoma. However, no mutations have been identi®ed in VHL interacting proteins in wild type VHL tumors. We previously reported that the TRC8 gene was interrupted by a t(3;8) translocation in a family with hereditary renal and non-medullary thyroid cancer. TRC8 encodes a multi-membrane spanning protein containing a RING-H2 ®nger with in vitro ubiquitin ligase activity. We isolated the Drosophila homologue, DTrc8, and studied its function by genetic manipulations and a yeast 2-hybrid screen. Human and Drosophila TRC8 proteins localize to the endoplasmic reticulum. Loss of either DTrc8 or DVhl resulted in an identical ventral midline defect. Direct interaction between DTrc8 and DVhl was con®rmed by GST-pulldown and co-immunoprecipitation experiments. CSN-5/JAB1 is a component of the COP9 signalosome, recently shown to regulate SCF function. We found that DTrc8 physically interacts with CSN-5 and that human JAB1 localization is dependent on VHL mutant status. Lastly, overexpression of DTrc8 inhibited growth consistent with its presumed role as a tumor suppressor gene. Thus, VHL, TRC8, and JAB1 appear to be linked both physically and functionally and all three may participate in the development of kidney cancer.

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway

et al. 2002

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“…(9,10) PTCH1 is composed of N-and C-terminal domains, two large extracellular and one large intracellular loops, and 12-pass transmembrane domains, two to six of which form the putative sterol-sensing domain (SSD) considered to participate in vesicular trafficking of cholesterol and other lipids. (11,12) We and other groups have reported that more than 85% of patients with NBCCS harbor heterozygous germline PTCH1 mutations, (13)(14)(15) primarily consisting of PTCH1 protein truncations (73%) that are usually concentrated in the large extracellular and intracellular loops and in the N-terminal region. Germline missense mutations (17%) occur primarily in the transmembrane domains and especially in the SSDs.…”

Section: Introductionmentioning

confidence: 99%

Heterozygous PTCH1 Mutations Impact the Bone Metabolism in Patients With Nevoid Basal Cell Carcinoma Syndrome Likely by Regulating SPARC Expression

Hong

Zhang

et al. 2016

Journal of Bone and Mineral Research

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Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by bone and skin abnormalities and a predisposition to various tumors. Keratocystic odontogenic tumors (KCOTs), which are common tumors of the jaw that cause extensive damage to the jawbone, are usually accompanied with NBCCS. Germline PTCH1 mutations in NBCCS tumorigenesis have been frequently studied; however, little is known regarding the pathogenesis of bone abnormalities in this disease. This study sought to investigate the mechanism underlying heterozygous PTCH1 mutation-mediated abnormal bone metabolism in patients with NBCCS. Stromal cells were isolated from the fibrous capsules of patients with NBCCS-associated or non-syndromic keratocystic odontogenic tumors and non-syndromic tumor stromal cells without PTCH1 mutations served as controls. Germline PTCH1 heterozygous mutations were confirmed in all NBCCS samples and differential protein expression was identified using tandem mass tag-labeled proteomics analysis. Our findings revealed that osteonectin/SPARC expression was significantly downregulated in syndromic stromal cells compared with non-syndromic stromal cells. SPARC expression was even lower in stromal cells carrying PTCH1 protein truncation mutations. PTCH1 siRNA transfection demonstrated that SPARC downregulation correlates with decreased PTCH1 expression. Furthermore, exogenous SPARC promoted osteogenic differentiation of syndromic stromal cells with enhanced development of calcium nodules. In addition, bone mineral density tests showed that patients with NBCCS exhibit weak bone mass compared with sex-and age-matched controls. This study indicates that germline PTCH1 heterozygous mutations play a major role in bone metabolism in patients with NBCCS, in particular in those with PTCH1 protein truncation mutations. SPARC may represent an important downstream modulator of PTCH1 mediation of bone metabolism. Thus, bone mineral density monitoring is critical for patients with NBCCS for prevention of osteoporosis. In addition, surgical procedures on syndromic-associated KCOTs should be performed with consideration of the weaker bone mass in such patients.

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“…TRC8 is a multimembrane spanning ER-resident protein containing a RING-H2 finger with demonstrable E3-ubiquitin ligase activity (Lorick et al, 1999;Gemmill et al, 2002). In addition, it has partial similarity to the Hedgehog receptor, Patched (Gemmill et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…While most familial RCC cases are caused by mutations in the VHL (von Hippel-Lindau) gene, affected individuals in this family lacked germline VHL mutations and other manifestations of VHL syndrome. The (3;8) rearrangement fuses 5 0 -untranslated FHIT sequences with the C-terminal coding portion of TRC8 (translocation in renal cancer from chromosome 8), interrupting a predicted sterolsensing domain (Gemmill et al, 1998). TRC8 is a multimembrane spanning ER-resident protein containing a RING-H2 finger with demonstrable E3-ubiquitin ligase activity (Lorick et al, 1999;Gemmill et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Growth suppression induced by the TRC8 hereditary kidney cancer gene is dependent upon JAB1/CSN5

et al. 2005

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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 CSN4 null 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.

show abstract

The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched- related gene, TRC8

Cited by 142 publications

References 48 publications

The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway

The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway

Heterozygous PTCH1 Mutations Impact the Bone Metabolism in Patients With Nevoid Basal Cell Carcinoma Syndrome Likely by Regulating SPARC Expression

Growth suppression induced by the TRC8 hereditary kidney cancer gene is dependent upon JAB1/CSN5

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