Transcript Level Modulates the Inherent Oncogenicity of RET/PTC Oncoproteins

Abstract

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. [Cancer Res 2009;69(11):4861-9]

RET PLCγ Phosphotyrosine Binding Domain Regulates Ca2+ Signaling and Neocortical Neuronal Migration

“…Thus, RET regulated Ca 2+ signaling may be involved in Hirschsprung's disease and MEN2a/b. In the case of RET as an oncogene the results presented herein might be of clinical benefit as cytosolic Ca 2+ signaling is implicated in general cancer growth as well as in thyroid cancers of the MEN2b type [30], [34], [35]. Tumor cell proliferation has recently been reported in papillary thyroid carcinoma through a signaling pathway where RET, MAPK, and CaMKII contributes [15].…”

Absence of BRAF, NRAS, KRAS, HRAS Mutations, and RET/PTC Gene Rearrangements Distinguishes Dominant Nodules in Hashimoto Thyroiditis from Papillary Thyroid Carcinomas

“…RET translocations are common in papillary thyroid carcinomas, and levels of RET oncogene expression correlate with clinical behavior [2,24]. Additionally, there have been conflicting reports as to whether RET-PTC fusion gene products are expressed in HT and whether these might serve as an initiating event for tumorigenesis in HT [5,23,28,35].…”

Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2

“…These mutant RET dimers are constitutively active in the absence of ligands. Furthermore, mutant dimers are not recruited to lipid rafts through GFRα interactions, and may be activated in other membrane compartments, which can affect the nature and intensity of the resultant downstream signals (36),(37). Downstream signaling regulation, via interactions with ubiquitin ligases such as CasitasB-lineage lymphoma proto-oncogene (CBL) (38), or with cellular phosphatases such as SHP1 and SHP2 (39),(40) that are involved in limiting or terminating signals, differ from that of the raft-associated wild-type receptor, enhancing the effect of the oncogenic mutation.…”

“…RET signaling from intracellular compartments may differ (in intensity or otherwise) from that at the plasma membrane, which has been shown to be the case when wild-type RET is internalized into endosomes following ligand stimulation (57) and for cytosolic RET mutants found in papillary thyroid carcinoma (37). …”