RING-dependent tumor suppression and G2/M arrest induced by the TRC8 hereditary kidney cancer gene

Brauweiler, Anne; Lorick, Kevin L.; Lee, J P; Tsai, Ya Chea; Chan, Daniel C.; Weissman, Allan M.; Drabkin, Harry A.; Gemmill, Robert M.

doi:10.1038/sj.onc.1210017

Cited by 37 publications

(48 citation statements)

References 28 publications

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“…6C). As negative controls, we used a mutant of TRC8 with the point mutations C547A and C550A in its RING domain to abolish activity (RING-mut) and another with the RING domain truncated (containing residues 1-491, ⌬RING) (32,46). The TRC8-RING-mut had no effect on CG hERG, but it still caused some decrease in FG hERG, whereas the TRC8-⌬RING had no effect at all (Fig.…”

Section: E2-conjugating Enzyme Ube2g2mentioning

confidence: 99%

“…These data provide the first indication that TRC8 is a quality control E3 ligase and raise the question of how it recognizes hERG. TRC8 has several transmembrane helices, followed by a C-terminal cytosolic region containing the RING domain (46,47), and it could bind hERG through either or both of these parts. The interaction was therefore addressed by co-precipitation of the transfected TRC8 constructs with hERG.…”

Section: Journal Of Biological Chemistry 2293mentioning

confidence: 99%

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Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels

Hantouche

Williamson

Valinsky

et al. 2017

Journal of Biological Chemistry

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Edited by George N. DeMartinoCardiac long QT syndrome type 2 is caused by mutations in the human ether a go-go-related gene (hERG) potassium channel, many of which cause misfolding and degradation at the endoplasmic reticulum instead of normal trafficking to the cell surface. The Hsc70/Hsp70 chaperones assist the folding of the hERG cytosolic domains. Here, we demonstrate that the Hsp70 nucleotide exchange factor Bag1 promotes hERG degradation by the ubiquitin-proteasome system at the endoplasmic reticulum to regulate hERG levels and channel activity. Dissociation of hERG complexes containing Hsp70 and the E3 ubiquitin ligase CHIP requires the interaction of Bag1 with Hsp70, but this does not involve the Bag1 ubiquitin-like domain. The interaction with Bag1 then shifts hERG degradation to the membrane-anchored E3 ligase TRC8 and its E2-conjugating enzyme Ube2g2, as determined by siRNA screening. TRC8 interacts through the transmembrane region with hERG and decreases hERG functional expression. TRC8 also mediates degradation of the misfolded hERG-G601S disease mutant, but pharmacological stabilization of the mutant structure prevents degradation. Our results identify TRC8 as a previously unknown Hsp70-independent quality control E3 ligase for hERG.

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Section: E2-conjugating Enzyme Ube2g2mentioning

confidence: 99%

Section: Journal Of Biological Chemistry 2293mentioning

confidence: 99%

Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels

Hantouche

Williamson

Valinsky

et al. 2017

Journal of Biological Chemistry

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“…Collectively, these results show that TRC8 is essential for MHC I dislocation and al., 2002) predicted to span the membrane up to 10 times. Its C terminus has the defining feature of RING-type E3 ligases, a RING-H2 domain which coordinates zinc binding and was shown to catalyze in vitro ubiquitination (Brauweiler et al, 2007). To assess the requirement for a functional RING on TRC8 in vivo activity, we compared overexpression of wildtype and TRC8 RING mutants on cell surface MHC I levels in US2-expressing HeLa cells.…”

Section: Trc8 Depletion Rescues Mhc I From the Cytosol To The Membranmentioning

confidence: 99%

“…To identify potential TRC8-binding partners, doxycycline-induced, HA-tagged TRC8 RING mutant HEK-293 cells (Brauweiler et al, 2007) transfected with US2 were radiolabeled and immunoprecipitated with anti-HA antibody (Fig. 4 A, lane 1).…”

Section: Trc8 Associates In the Er With Us2 Mhc I And Sspmentioning

confidence: 99%

The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER

Martyn¹,

Boomen²,

Wiertz³

et al. 2009

J Exp Med

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“…In acute myeloid leukemia (AML), patients with high expression of miR-191 have significantly worse overall and event-free survival than AML patients with low expression (20). Furthermore, PLCD1 and RNF139, two predicted candidate target genes of miR-191, are tumor suppressors in esophageal squamous cell carcinoma and human hereditary kidney cancer, respectively (21,22). miR-93 is up-regulated in gastric cancer tissues compared to the corresponding normal tissues (23).…”

Section: Discussionmentioning

confidence: 99%

5-Fluorouracil and oxaliplatin modify the expression profiles of microRNAs in human colon cancer cells in vitro

Bai¹

2009

Oncol Rep

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Abstract. MicroRNAs (miRNAs) have recently taken center stage in the field of human molecular oncology. Most of the chemotherapeutics are able to interfere with nucleic acid metabolism and gene expression. The purpose of this study was to determine how 5-fluorouracil (5-FU) and oxaliplatin (L-OHP) modify the expression profiles of miRNAs in HCT-8 and HCT-116 colon cancer cells and whether the pharmacodynamic mechanisms of the chemotherapeutics could rely in part on their influence on miRNA expression. The expression profiles of miRNAs were determined using a miRNA microarray containing 856 human miRNA probes. The expression of selected miRNAs was then validated by real-time RT-PCR. Fifty-six up-and 50 down-regulations of miRNA expression with statistical significance were identified in colon cancer cells following exposure to 5-FU or L-OHP compared to matched control cells. The down-regulations of miR-197, miR-191, miR-92a, miR-93, miR-222 and miR-1826, whose expression was significantly down-regulated in both cell lines after the treatment of one drug or in one cell line following exposure to either drug, were further validated. Analysis of the relevant literature indicated that, in line with the tumor suppressive activity of 5-FU and L-OHP, the six down-regulated miRNAs might function as oncogenes due to their overexpression in cancers, and some of them correlated with the poor prognosis and treatment-resistance of cancer. In conclusion, we identify the modification of miRNA expression profiles in colon cancer cells following exposure to 5-FU and L-OHP, and our results indicate that their pharmacodynamic mechanisms could rely in part on their influence on the down-regulated miRNA expression.Further studies are needed to determine whether these miRNAs and their target genes might potentially provide for novel molecular markers and act as novel targets for treatment by interference.

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RING-dependent tumor suppression and G2/M arrest induced by the TRC8 hereditary kidney cancer gene

Cited by 37 publications

References 28 publications

Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels

Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels

The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER

5-Fluorouracil and oxaliplatin modify the expression profiles of microRNAs in human colon cancer cells in vitro

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