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The DNA rearrangement that generates the TRK-T3 oncogene involves a novel gene on chromosome 3 whose product has a
A Greco1, C Mariani, C Miranda
1Division of Experimental Oncology A, Istituto Nazionale Tumori, Milan, Italy.
Abstract:
Oncogenic rearrangements of the NTRK1 gene (also designated TRKA), encoding one of the receptors for the nerve growth factor, are frequently detected in thyroid carcinomas. Such rearrangements fuse the NTRK1 tyrosine kinase domain to 5'-end sequences belonging to different genes. In previously reported studies we have demonstrated that NTRK1 oncogenic activation involves two genes, TPM3 and TPR, both localized similarly to the receptor tyrosine kinase, on the q arm of chromosome 1. Here we report the characterization of a novel NTRK1-derived thyroid oncogene, named TRK-T3. A cDNA clone, capable of transforming activity, was isolated from a transformant cell line. Sequence analysis revealed that TRK-T3 contains 1,412 nucleotides of NTRK1 preceded by 598 nucleotides belonging to a novel gene that we have named TFG (TRK-fused gene). The TRK-T3 amino acid sequence displays, within the TFG region, a coiled-coil motif that could endow the oncoprotein with the capability to form complexes. The TRK-T3 oncogene encodes a 68-kDa cytoplasmic protein reacting with NTRK1-specific antibodies. By sedimentation gradient experiments the TRK-T3 oncoprotein was shown to form, in vivo, multimeric complexes, most likely trimers or tetramers. The TFG gene is ubiquitously expressed and is located on chromosome 3. The breakpoint producing the TRK-T3 oncogene occurs within exons of both the TFG gene and the NTRK1 gene and produces a chimeric exon that undergoes alternative splicing. Molecular analysis of the NTRK1 rearranged fragments indicated that the chromosomal rearrangement is reciprocal and balanced and involves loss of a few nucleotides of germ line sequences.
Insights
Researchers identified a new NTRK1 gene rearrangement, TRK-T3, in thyroid cancer. This oncogene results from a fusion between the TFG and NTRK1 genes, forming a novel oncoprotein that can assemble into complexes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- NTRK1 gene rearrangements are common in thyroid carcinomas.
- These rearrangements fuse the NTRK1 tyrosine kinase domain with other genes.
- Previous studies identified TPM3 and TPR as fusion partners for NTRK1.
Purpose of the Study:
- To characterize a novel NTRK1-derived oncogene in thyroid cancer.
- To identify and analyze the TFG gene as a new fusion partner for NTRK1.
Main Methods:
- Isolation and sequencing of a transforming cDNA clone (TRK-T3).
- Sequence analysis to identify fusion partners and protein motifs.
- Western blot analysis using NTRK1-specific antibodies.
- Sedimentation gradient experiments to study protein complex formation.
Main Results:
- A novel oncogene, TRK-T3, was identified, resulting from a fusion between the TFG and NTRK1 genes.
- TRK-T3 encodes a 68-kDa cytoplasmic protein with a coiled-coil motif in the TFG region.
- The TRK-T3 oncoprotein forms multimeric complexes (trimers/tetramers) in vivo.
- The TFG gene is ubiquitously expressed and located on chromosome 3.
- The fusion involves a chimeric exon with alternative splicing and a balanced reciprocal chromosomal rearrangement.
Conclusions:
- TRK-T3 represents a novel oncogenic fusion protein in thyroid carcinoma.
- The TFG-NTRK1 fusion may contribute to thyroid tumorigenesis through complex formation.
- Understanding these rearrangements aids in targeted therapy development for NTRK1-altered cancers.