Transcript level modulates the inherent oncogenicity of RET/PTC oncoproteins.
Mutations to the RET proto-oncogene occur in as many as one in three cases of thyroid cancer and have been detected in both the medullary (MTC) and the papillary (PTC) forms of the disease. Of the nearly 400 chromosomal rearrangements resulting in oncogenic fusion proteins that have been identified to date, the rearrangements that give rise to RET fusion oncogenes in PTC remain the paradigm for chimeric oncoprotein involvement in solid tumors. RET-associated PTC tumors are phenotypically indolent and relatively less aggressive than RET-related MTCs. The mechanism(s) contributing to the differences in oncogenicity of RET-related MTC and PTC remains unexplained. Here, through cellular and molecular characterization of the two most common RET/PTC rearrangements (PTC1 and PTC3), we show that RET/PTC oncoproteins are highly oncogenic when overexpressed, with the ability to increase cell proliferation and transformation. Further, RET/PTCs activate similar downstream signaling cascades to wild-type RET, although at different levels, and are relatively more stable as they avoid lysosomal degradation. Absolute quantitation of transcript levels of RET, CCDC6, and NCOA4 (the 5' fusion genes involved in PTC1 and PTC3, respectively) suggest that these rearrangements result in lower RET expression in PTCs relative to MTCs. Together, our findings suggest PTC1 and PTC3 are highly oncogenic proteins when overexpressed, but result in indolent disease compared with RET-related MTCs due to their relatively low expression from the NCOA4 and CCDC6 promoters in vivo.
Richardson
Douglas S
DS
Department of Pathology and Molecular Medicine, Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
Gujral
Taranjit S
TS
Peng
Susan
S
Asa
Sylvia L
SL
Mulligan
Lois M
LM
D018276:Carcinoma, Medullary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D055503:Protein Multimerization; D021381:Protein Transport; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology
C088832:CCDC6 protein, human; D003598:Cytoskeletal Proteins; C000715470:MAS1 protein, human; C111382:NCOA4 protein, human; D009363:Neoplasm Proteins; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D014157:Transcription Factors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human