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Published Online January 22, 2009
Science DOI: 10.1126/science.1157669

Reports

Submitted on March 12, 2008
Accepted on January 14, 2009

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

Jiang Liu 1{dagger}, Murad Ghanim 2{dagger}, Lei Xue 3{dagger}, Christopher D. Brown 1, Ivan Iossifov 4, Cesar Angeletti 5, Sujun Hua 1, Nicholas Nègre 1, Michael Ludwig 6, Thomas Stricker 7, Hikmat A. Al-Ahmadie 8, Maria Tretiakova 8, Robert L. Camp 5, Montse Perera-Alberto 9, David L. Rimm 5, Tian Xu 3, Andrey Rzhetsky 10, Kevin P. White 6*

1 Institute for Genomics and Systems Biology, The University of Chicago and Argonne National Laboratory, Chicago, IL, USA.; Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
2 Institute for Genomics and Systems Biology, The University of Chicago and Argonne National Laboratory, Chicago, IL, USA.; Department of Human Genetics, The University of Chicago, Chicago, IL, USA.; Present address: Department of Entomology, The Volcani Center, Bet Dagan, Israel.
3 Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
4 Institute for Genomics and Systems Biology, The University of Chicago and Argonne National Laboratory, Chicago, IL, USA.; Department of Medicine, The University of Chicago, Chicago, IL, USA.; Present address: Cold Spring Harbor Laboratory, One Bungtown Road, P.O. Box 100, Cold Spring Harbor, NY 11742, USA.
5 Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
6 Institute for Genomics and Systems Biology, The University of Chicago and Argonne National Laboratory, Chicago, IL, USA.; Department of Human Genetics, The University of Chicago, Chicago, IL, USA.; Department of Ecology and Evolution, The University of Chicago, Chicago, IL, USA.
7 Institute for Genomics and Systems Biology, The University of Chicago and Argonne National Laboratory, Chicago, IL, USA.; Department of Human Genetics, The University of Chicago, Chicago, IL, USA.; Department of Pathology, The University of Chicago, Chicago, IL, USA.
8 Department of Pathology, The University of Chicago, Chicago, IL, USA.
9 Department of Anatomy, La Laguna University, La Laguna, Tenerife, Spain.
10 Institute for Genomics and Systems Biology, The University of Chicago and Argonne National Laboratory, Chicago, IL, USA.; Department of Medicine, The University of Chicago, Chicago, IL, USA.

* To whom correspondence should be addressed.
Kevin P. White , E-mail: kpwhite{at}uchicago.edu

{dagger}These authors contributed equally to this work.

We constructed a large-scale functional network model in Drosophila elanogaster 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 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 carcinoma (RCC), 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.


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Science. ISSN 0036-8075 (print), 1095-9203 (online)