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

Science. 2009 Feb 27;323(5918):1218-22. doi: 10.1126/science.1157669. Epub 2009 Jan 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Drosophila Proteins
  • Fushi Tarazu Transcription Factors
  • Homeodomain Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • SPOP protein, human
  • Transcription Factors
  • eve protein, Drosophila
  • ftz protein, Drosophila
  • Janus Kinases
  • puc protein, Drosophila
  • Phosphoprotein Phosphatases

Associated data

  • GEO/GSE14086
  • GEO/GSE14289