Analysis of Drosophila segmentation network identifies a JNK pathway factor overexpressed in kidney cancer

Liu, J., Ghanim, M., Xue, L., Brown, C. D., Iossifov, I., Angeletti, C., Hua, S., Negre, N., Ludwig, M., Stricker, T., Al-Ahmadie, H. A., Tretiakova, M., Camp, R. L., Perera-Alberto, M., Rimm, D. L., Xu, T., Rzhetsky, A., White, K. P. (February 2009) Analysis of Drosophila segmentation network identifies a JNK pathway factor overexpressed in kidney cancer. Science, 323 (5918). pp. 1218-22. ISSN 1095-9203 (Electronic)0036-8075 (Linking)

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DOI: 10.1126/science.1157669


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.

Item Type: Paper
Uncontrolled Keywords: Amino Acid Sequence Animals Apoptosis Carcinoma, Renal Cell/ genetics/metabolism Cell Line Compound Eye, Arthropod/embryology/metabolism Drosophila Proteins/genetics/metabolism Drosophila melanogaster/embryology/ genetics/metabolism Embryo, Nonmammalian/metabolism Fushi Tarazu Transcription Factors/genetics/metabolism Gene Expression Profiling Gene Regulatory Networks Homeodomain Proteins/genetics/metabolism Humans Janus Kinases/ metabolism Kidney/metabolism Kidney Neoplasms/ genetics/metabolism Molecular Sequence Data Nervous System/embryology Nuclear Proteins/ genetics/metabolism Phosphoprotein Phosphatases/metabolism Phosphorylation Repressor Proteins/ genetics/metabolism Signal Transduction Transcription Factors/genetics/metabolism Transcription, Genetic
Subjects: diseases & disorders > cancer
organism description > animal > insect > Drosophila
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > tumor necrosis factor
CSHL Authors:
Communities: CSHL labs > Iossifov lab
Depositing User: Matt Covey
Date: 27 February 2009
Date Deposited: 01 Apr 2015 20:23
Last Modified: 03 Oct 2019 13:31
PMCID: PMC2756524
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