The INT6 cancer gene and MEK signaling pathways converge during zebrafish development.
BACKGROUND
Int-6 (integration site 6) was identified as an oncogene in a screen of tumorigenic mouse mammary tumor virus (MMTV) insertions. INT6 expression is altered in human cancers, but the precise role of disrupted INT6 in tumorigenesis remains unclear, and an animal model to study Int-6 physiological function has been lacking.


RESULTS
Here, we create an in vivo model of Int6 function in zebrafish, and through genetic and chemical-genetic approaches implicate Int6 as a tissue-specific modulator of MEK-ERK signaling. We find that Int6 is required for normal expression of MEK1 protein in human cells, and for Erk signaling in zebrafish embryos. Loss of either Int6 or Mek signaling causes defects in craniofacial development, and Int6 and Erk-signaling have overlapping domains of tissue expression.


CONCLUSIONS
Our results provide new insight into the physiological role of vertebrate Int6, and have implications for the treatment of human tumors displaying altered INT6 expression.
Grzmil
Michal
M
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
Whiting
Danny
D
Maule
John
J
Anastasaki
Corina
C
Amatruda
James F
JF
Kelsh
Robert N
RN
Norbury
Chris J
CJ
Patton
E Elizabeth
EE
D000818:Animals; D045744:Cell Line, Tumor; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000254:growth & development; D029961:Zebrafish Proteins / Q000235:genetics* / Q000502:physiology
D039621:Eukaryotic Initiation Factor-3; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D029961:Zebrafish Proteins; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human