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Science 323 (5918): 1218-1222

Copyright © 2009 by the American Association for the Advancement of Science

Analysis of Drosophila Segmentation Network Identifies a JNK Pathway Factor Overexpressed in Kidney Cancer

Jiang Liu,1,2* Murad Ghanim,1,2*{dagger} Lei Xue,3* Christopher D. Brown,1,2 Ivan Iossifov,1,4{ddagger} Cesar Angeletti,5 Sujun Hua,1,2 Nicolas Nègre,1,2 Michael Ludwig,1,2,6 Thomas Stricker,1,2,7 Hikmat A. Al-Ahmadie,7 Maria Tretiakova,7 Robert L. Camp,5 Montse Perera-Alberto,8 David L. Rimm,5 Tian Xu,3 Andrey Rzhetsky,1,4 Kevin P. White1,2,6§

Abstract: We constructed a large-scale functional network model in Drosophila melanogaster built around two key transcription factors involved in the process of embryonic segmentation. Analysis of the model allowed the identification of a new role for the ubiquitin E3 ligase complex factor SPOP. In Drosophila, the gene encoding SPOP is a target of segmentation transcription factors. Drosophila SPOP mediates degradation of the Jun kinase phosphatase Puckered, thereby inducing tumor necrosis factor (TNF)/Eiger–dependent apoptosis. In humans, we found that SPOP plays a conserved role in TNF-mediated JNK signaling and was highly expressed in 99% of clear cell renal cell carcinomas (RCCs), the most prevalent form of kidney cancer. SPOP expression distinguished histological subtypes of RCC and facilitated identification of clear cell RCC as the primary tumor for metastatic lesions.

1 Institute for Genomics and Systems Biology, The University of Chicago and Argonne National Laboratory, Chicago, IL 60637, USA.
2 Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA.
3 Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, C T 06519, USA.
4 Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
5 Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
6 Department of Ecology and Evolution, The University of Chicago, Chicago, IL 60637, USA.
7 Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
8 Department of Anatomy, La Laguna University, La Laguna, 38320 Tenerife, Spain.

* These authors contributed equally to this work.

{dagger} Present address: Department of Entomology, The Volcani Center, Bet Dagan, Israel.

{ddagger} Present address: Cold Spring Harbor Laboratory, One Bungtown Road, P.O. Box 100, Cold Spring Harbor, NY 11742, USA.

§ To whom correspondence should be addressed. E-mail: kpwhite{at}uchicago.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies.
L. N. Micel, J. J. Tentler, P. G. Smith, and G. S. Eckhardt (2013)
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Machine Science.
J. Evans and A. Rzhetsky (2010)
Science 329, 399-400
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Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase.
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