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

Liu J, Ghanim M, Xue L, Brown CD, Iossifov I, Angeletti C, Hua S, Nègre N, Ludwig M, Stricker T, Al-Ahmadie HA, Tretiakova M, Camp RL, Perera-Alberto M, Rimm DL, Xu T, Rzhetsky A, White KP
Science. 2009 323 (5918): 1218-22

PMID: 19164706 · PMCID: PMC2756524 · 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.

MeSH Terms (26)

Amino Acid Sequence Animals Apoptosis Carcinoma, Renal Cell Cell Line Compound Eye, Arthropod Drosophila melanogaster Drosophila Proteins Embryo, Nonmammalian Fushi Tarazu Transcription Factors Gene Expression Profiling Gene Regulatory Networks Homeodomain Proteins Humans Janus Kinases Kidney Kidney Neoplasms Molecular Sequence Data Nervous System Nuclear Proteins Phosphoprotein Phosphatases Phosphorylation Repressor Proteins Signal Transduction Transcription, Genetic Transcription Factors

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