Analysis of Drosophila segmentation network identifies a JNK pathway factor overexpressed in kidney cancer.
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.
Liu
Jiang
J
Institute for Genomics and Systems Biology, University of Chicago and Argonne National Laboratory, Chicago, IL 60637, USA.
Ghanim
Murad
M
Xue
Lei
L
Brown
Christopher D
CD
Iossifov
Ivan
I
Angeletti
Cesar
C
Hua
Sujun
S
Nègre
Nicolas
N
Ludwig
Michael
M
Stricker
Thomas
T
Al-Ahmadie
Hikmat A
HA
Tretiakova
Maria
M
Camp
Robert L
RL
Perera-Alberto
Montse
M
Rimm
David L
DL
Xu
Tian
T
Rzhetsky
Andrey
A
White
Kevin P
KP
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D054910:Compound Eye, Arthropod / Q000196:embryology / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D051717:Fushi Tarazu Transcription Factors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009420:Nervous System / Q000196:embryology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D029721:Drosophila Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C509761:SPOP protein, human; D014157:Transcription Factors; C052837:eve protein, Drosophila; C497169:ftz protein, Drosophila; D053612:Janus Kinases; C110854:puc protein, Drosophila; D010749:Phosphoprotein Phosphatases