Characterization of the NTRK1 Genomic Region Involved in Chromosomal Rearrangements Generating TRK Oncogenes

Greco, Angela; Mariani, Cristina; Miranda, Claudia; Pagliardini, Sonia; Pierotti, Marco A.

doi:10.1006/geno.1993.1482

Cited by 41 publications

(37 citation statements)

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“…Poly(A) ϩ RNA was purified by using the Quick Prep mRNA purification kit (Pharmacia) as suggested by the manufacturer. The different NTRK1-specific probes, kindly provided by M. Barbacid, comprised plasmid pLM6, containing the full-length cDNA (22), and plasmids pDM56 and pDM17, containing the 5Ј and the 3Ј moieties of the gene, respectively (10).…”

Section: Methodsmentioning

confidence: 99%

The DNA Rearrangement That Generates the TRK-T3 Oncogene Involves a Novel Gene on Chromosome 3 Whose Product Has a Potential Coiled-Coil Domain

Greco¹,

Mariani²,

Miranda³

et al. 1995

Molecular and Cellular Biology

190

172

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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.Chromosomal rearrangements producing chimeric oncogenes are frequently associated with human cancer, and several lines of evidence suggest that they are involved in the pathogenesis of their respective tumors (31).Among solid tumors, papillary thyroid carcinoma provides a unique model of a frequent generation of chimeric oncogenes. In this type of neoplasia, in fact, two proto-oncogenes, RET and NTRK1 (also named TRKA), have been found rearranged in about 50% of the samples assayed (5). RET and NTRK1 both encode transmembrane receptor tyrosine kinases (RTKs), whose expression is highly tissue specific, being restricted to specific components of the peripheral nervous system (1, 38, 40). The common mechanism of activation is represented by somatic rearrangements juxtaposing their tyrosine kinase (TK) domain to 5Ј-end sequences derived from unrelated loci and producing chimeric oncogenes whose products display a constitutive and ectopic TK enzymatic activity (29).The NTRK1 gene encodes one of the receptors for the nerve growth factor (NGF) (15, 16) and is located on the q arm of chromosome 1 (24, 26). NTRK1 was originally detected as an oncogene in a human colon carcinoma; this activated version of the gene was generated by a chromosomal rearrangement fusing the NTRK1 TK domain with sequences of a tropomyosin gene, TPM3, and was designated the ''TRK oncogene'' (21).Afterwards, ...

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Section: Methodsmentioning

confidence: 99%

The DNA Rearrangement That Generates the TRK-T3 Oncogene Involves a Novel Gene on Chromosome 3 Whose Product Has a Potential Coiled-Coil Domain

Greco¹,

Mariani²,

Miranda³

et al. 1995

Molecular and Cellular Biology

190

172

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“…The elimination of the carbonyl contact to give aniline compound 12 resulted in complete loss of activity as expected for a classic type II DFG-out inhibitor where the amide makes a hydrogen bond contact with the DFG aspartate and glutamate in helix c. 26 Replacement of the pyrrole with other groups (pyrrolidine, isooxazole, and cyclopentane) resulted in loss of activity. Methylation of the pyrrole nitrogen of compound 5 yielded a significantly less potent compound (13), suggesting that the pyrrole NH may be involved in a key interaction at the protein hinge region. Decoration on the pyrrole ring led to compounds of varying potency (14−19).…”

mentioning

confidence: 99%

Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models

Albaugh

Fan

et al. 2012

ACS Med. Chem. Lett.

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Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified. Optimization led to the identification of GNF-5837 (22), a potent, selective, and orally bioavailable pan-TRK inhibitor that inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF. The properties of 22 make it a good tool for the elucidation of TRK biology in cancer and other nononcology indications.

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“…Based on their size, and estimations that were made for the distance between SPTA1 and FcERIA (Kingsmore et al 1989), these YACs must be extending for the largest part distal to the SPTA1 marker, and thUvS, away from the breakpoint. NRTK1, which maps to lq21-22 (Weier et al 1995), has been reported to form the irk oncogene by linkage of the tyrosine kinase domain to foreign activating se quences (Martin-Zanca et al 3989;Greco et al 1993). Based on its function, it is a possible candidate in this re gion.…”

Section: Ap0a2mentioning

confidence: 99%

Fine mapping of the 1q21 breakpoint of the papillary renal cell carcinoma-associated (X;1) translocation

et al. 1996

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A combination of Southern blot analysis on a lary RCCs. The cytoplasm of this tumor type shows marked panel of tumor-derived somatic cell hybrids and fluores cence in situ hybridization (FISH) techniques was used to map a series of DNA markers relative to the 1 q21 break point of the renal cell carcinoma (RCC)-associated (X;l)-(pll;q21) translocation. This breakpoint maps between several members of the S 100 family which are clustered in the lq2l region and a conserved region between man and mouse containing the markers SPTA1-CRP-APCSFcER 1 A-ATP 1A2-APO A2. The location of the break point coincides with the transition of a region of synteny of human chromosome 1 with mouse chromosomes 3 and 1.

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Characterization of the NTRK1 Genomic Region Involved in Chromosomal Rearrangements Generating TRK Oncogenes

Cited by 41 publications

References 0 publications

The DNA Rearrangement That Generates the TRK-T3 Oncogene Involves a Novel Gene on Chromosome 3 Whose Product Has a Potential Coiled-Coil Domain

The DNA Rearrangement That Generates the TRK-T3 Oncogene Involves a Novel Gene on Chromosome 3 Whose Product Has a Potential Coiled-Coil Domain

Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models

Fine mapping of the 1q21 breakpoint of the papillary renal cell carcinoma-associated (X;1) translocation

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