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

Robert M. Gemmill, Lynne T. Bemis, Jason P. Lee, M. Ali Sozen, Chan Zeng, Paul F. Erickson, Joan E. Hooper, Harry A. Drabkin

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

VHL is part of an SCF related E3-ubiquitin ligase complex with 'gatekeeper' function in renal carcinoma. However, no mutations have been identified 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 finger 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 confirmed 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-S 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.

Original languageEnglish (US)
Pages (from-to)3507-3516
Number of pages10
JournalOncogene
Volume21
Issue number22
DOIs
StatePublished - Jan 1 2002

Fingerprint

Kidney Neoplasms
Neoplasm Genes
Kidney
Ubiquitin-Protein Ligases
Ligases
Growth
Ubiquitin
Tumor Suppressor Genes
Thyroid Neoplasms
Immunoprecipitation
Endoplasmic Reticulum
Fingers
Drosophila
Membrane Proteins
Yeasts
Carcinoma
Mutation
Genes
Neoplasms
Proteins

Keywords

  • JAB1/CSN-5
  • Patched
  • RING-H2 finger
  • Renal cell carcinoma
  • TRC8
  • VHL

Cite this

Gemmill, R. M., Bemis, L. T., Lee, J. P., Sozen, M. A., Zeng, C., Erickson, P. F., ... Drabkin, H. A. (2002). The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway. Oncogene, 21(22), 3507-3516. https://doi.org/10.1038/sj.onc.1205437

The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway. / Gemmill, Robert M.; Bemis, Lynne T.; Lee, Jason P.; Sozen, M. Ali; Zeng, Chan; Erickson, Paul F.; Hooper, Joan E.; Drabkin, Harry A.

In: Oncogene, Vol. 21, No. 22, 01.01.2002, p. 3507-3516.

Research output: Contribution to journalArticle

Gemmill, RM, Bemis, LT, Lee, JP, Sozen, MA, Zeng, C, Erickson, PF, Hooper, JE & Drabkin, HA 2002, 'The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway', Oncogene, vol. 21, no. 22, pp. 3507-3516. https://doi.org/10.1038/sj.onc.1205437
Gemmill, Robert M. ; Bemis, Lynne T. ; Lee, Jason P. ; Sozen, M. Ali ; Zeng, Chan ; Erickson, Paul F. ; Hooper, Joan E. ; Drabkin, Harry A. / The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway. In: Oncogene. 2002 ; Vol. 21, No. 22. pp. 3507-3516.
@article{6441f6e1d5144d46aca10d90e6278a4e,
title = "The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway",
abstract = "VHL is part of an SCF related E3-ubiquitin ligase complex with 'gatekeeper' function in renal carcinoma. However, no mutations have been identified 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 finger 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 confirmed 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-S 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.",
keywords = "JAB1/CSN-5, Patched, RING-H2 finger, Renal cell carcinoma, TRC8, VHL",
author = "Gemmill, {Robert M.} and Bemis, {Lynne T.} and Lee, {Jason P.} and Sozen, {M. Ali} and Chan Zeng and Erickson, {Paul F.} and Hooper, {Joan E.} and Drabkin, {Harry A.}",
year = "2002",
month = "1",
day = "1",
doi = "10.1038/sj.onc.1205437",
language = "English (US)",
volume = "21",
pages = "3507--3516",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "22",

}

TY - JOUR

T1 - The TRC8 hereditary kidney cancer gene suppresses growth and functions with VHL in a common pathway

AU - Gemmill, Robert M.

AU - Bemis, Lynne T.

AU - Lee, Jason P.

AU - Sozen, M. Ali

AU - Zeng, Chan

AU - Erickson, Paul F.

AU - Hooper, Joan E.

AU - Drabkin, Harry A.

PY - 2002/1/1

Y1 - 2002/1/1

N2 - VHL is part of an SCF related E3-ubiquitin ligase complex with 'gatekeeper' function in renal carcinoma. However, no mutations have been identified 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 finger 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 confirmed 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-S 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.

AB - VHL is part of an SCF related E3-ubiquitin ligase complex with 'gatekeeper' function in renal carcinoma. However, no mutations have been identified 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 finger 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 confirmed 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-S 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.

KW - JAB1/CSN-5

KW - Patched

KW - RING-H2 finger

KW - Renal cell carcinoma

KW - TRC8

KW - VHL

UR - http://www.scopus.com/inward/record.url?scp=0037118576&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037118576&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1205437

DO - 10.1038/sj.onc.1205437

M3 - Article

C2 - 12032852

AN - SCOPUS:0037118576

VL - 21

SP - 3507

EP - 3516

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 22

ER -