RET-mediated gene expression pattern is affected by isoform but not oncogenic mutation.
The inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2) is caused by mutations of the RET receptor tyrosine kinase and is characterized by medullary thyroid carcinoma. MEN 2 subtypes have distinct mutational spectrums and vary in severity. The most severe disease subtype, MEN 2B, is associated with a specific RET mutation (M918T) that has been predicted to alter downstream signaling and target gene expression patterns. We used gene expression microarray analysis to identify target genes modulated by RET. We compared two oncogenic RET mutants, associated with MEN 2A (2ARET) or MEN 2B (2BRET) disease subtypes, that are predicted to have distinct downstream target genes. We showed that overall, 2ARET and 2BRET modulated genes with similar functional ontologies. Further, when we validated our microarray data by quantitative real time PCR, we did not detect major differences in gene expression associated with these mutants when differences in receptor activity levels were considered. We did, however, detect differences in gene expression induced by two RET COOH-terminal isoforms, RET9 and RET51, irrespective of the RET form present (wildtype, 2ARET, or 2BRET). Our data suggest that similar transcriptional programs contribute to all forms of MEN 2 but that differences in target gene expression may contribute to developmental pattern differences observed between RET isoforms.
Hickey
Jessica G
JG
Division of Cancer Biology and Genetics, Cancer Research Institute Queen's University, Kingston, ON, Canada, K7L 3N6.
Myers
Shirley M
SM
Tian
Xuefei
X
Zhu
Shu Jun
SJ
V Shaw
Julie L
JL
Andrew
Scott D
SD
Richardson
Douglas S
DS
Brettschneider
Julia
J
Mulligan
Lois M
LM
D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D018814:Multiple Endocrine Neoplasia Type 2b / Q000235:genetics*; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics
D009363:Neoplasm Proteins; D020033:Protein Isoforms; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human