Grg1 acts as a lung-specific oncogene in a transgenic mouse model.
Groucho proteins are transcriptional corepressors that are recruited to gene regulatory regions by numerous transcription factors. Long isoforms, such as Grg1, have all the domains of the prototype Drosophila Groucho. Short Groucho proteins, such as Grg5, have only the amino-terminal Q and G/P domains. We generated Grg1 and Grg5 transgenic mice and found that Grg1 overexpression induces lung adenocarcinoma, whereas Grg5 overexpression does not. Coexpression of Grg5 with Grg1 reduces tumor burden. Grg1 and Grg5 both diminish p53 protein levels; however, only Grg1 overexpression induces elevated levels of ErbB1 and ErbB2 receptor tyrosine kinases. The molecular and biological changes that accompany tumor progression in Grg1 transgenic mice closely reiterate events seen in human lung cancer. We also found that within a human lung tumor tissue array, a significant number of carcinomas overexpress Grg1/TLE1. Our data suggest that Grg1 overexpression contributes to malignancy in human lung cancers.
Allen
Thaddeus
T
Molecular and Cellular Biology Division, Sunnybrook and Women's College Health Science Centre S-236, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.
van Tuyl
Minke
M
Iyengar
Pratibha
P
Jothy
Serge
S
Post
Martin
M
Tsao
Ming-Sound
MS
Lobe
Corrinne G
CG
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D056970:Co-Repressor Proteins; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D009857:Oncogenes; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism
D056970:Co-Repressor Proteins; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins; C499043:TLE1 protein, human; C434946:Tle1 protein, mouse