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1.
Int J Cancer ; 139(7): 1648-57, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27194579

RESUMO

The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose-limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160 mg/m(2) biweekly. Efficacy was evaluated in 15 patients with irinotecan-refractory colorectal cancer. The median time of disease control was 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13 of 19 patients. Matched pre- and posttreatment tumor biopsies showed decreased eIF4E mRNA levels in five of nine patients. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in seven of 15 (47%) patients who were progressing before study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre- and posttherapy tumor biopsies penetration of the ASO into the site of metastasis.


Assuntos
Camptotecina/análogos & derivados , Neoplasias Colorretais/terapia , Fator de Iniciação 4E em Eucariotos/antagonistas & inibidores , Oligonucleotídeos Antissenso/uso terapêutico , Oligorribonucleotídeos/uso terapêutico , Adulto , Idoso , Camptotecina/efeitos adversos , Camptotecina/sangue , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Terapia Combinada , Fator de Iniciação 4E em Eucariotos/genética , Feminino , Células HCT116 , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos , Oligonucleotídeos Antissenso/genética , Oligorribonucleotídeos/genética , RNA Mensageiro/sangue , RNA Mensageiro/genética
2.
Med Eng Phys ; 108: 103875, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36195354

RESUMO

High tibial osteotomy (HTO) is an effective surgical treatment for isolated medial compartment knee osteoarthritis; however, widespread adoption is limited due to difficulty in achieving the planned correction, and patient dissatisfaction due to soft tissue irritation. The aim of this study was to assess the accuracy of a novel HTO system with 3D printed patient specific implants and surgical guides using cadaveric specimens. Local ethics committee approval was obtained. The novel opening wedge HTO procedure was performed on eight cadaver leg specimens. Whole lower limb CT scans pre- and post-operatively provided geometrical assessment quantifying the discrepancy between pre-planned and post-operative measurements for key variables: the gap opening angle and the patient specific surgical instrumentation positioning. The average discrepancy between the pre-operative plan and the post-operative osteotomy correction angle was: 0.0 ±â€ˆ0.2° The R2 value for the regression correlation was 0.95. The average error in implant positioning was -0.4 ±â€ˆ4.3 mm, -2.6 ±â€ˆ3.4 mm and 3.1 ±â€ˆ1.7° vertically, horizontally, and rotationally respectively. This novel HTO surgery has greater accuracy in correction angle achieved compared to that reported for conventional or other patient specific methods with published data available. This system could potentially improve the accuracy of osteotomy correction angles achieved surgically.


Assuntos
Osteoartrite do Joelho , Tíbia , Humanos , Articulação do Joelho/cirurgia , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/cirurgia , Osteotomia/métodos , Impressão Tridimensional , Tíbia/cirurgia
3.
Bone Joint Res ; 7(12): 639-649, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30662711

RESUMO

OBJECTIVES: Opening wedge high tibial osteotomy (HTO) is an established surgical procedure for the treatment of early-stage knee arthritis. Other than infection, the majority of complications are related to mechanical factors - in particular, stimulation of healing at the osteotomy site. This study used finite element (FE) analysis to investigate the effect of plate design and bridging span on interfragmentary movement (IFM) and the influence of fracture healing on plate stress and potential failure. MATERIALS AND METHODS: A 10° opening wedge HTO was created in a composite tibia. Imaging and strain gauge data were used to create and validate FE models. Models of an intact tibia and a tibia implanted with a custom HTO plate using two different bridging spans were validated against experimental data. Physiological muscle forces and different stages of osteotomy gap healing simulating up to six weeks postoperatively were then incorporated. Predictions of plate stress and IFM for the custom plate were compared against predictions for an industry standard plate (TomoFix). RESULTS: For both plate types, long spans increased IFM but did not substantially alter peak plate stress. The custom plate increased axial and shear IFM values by up to 24% and 47%, respectively, compared with the TomoFix. In all cases, a callus stiffness of 528 MPa was required to reduce plate stress below the fatigue strength of titanium alloy. CONCLUSION: We demonstrate that larger bridging spans in opening wedge HTO increase IFM without substantially increasing plate stress. The results indicate, however, that callus healing is required to prevent fatigue failure.Cite this article: A. R. MacLeod, G. Serrancoli, B. J. Fregly, A. D. Toms, H. S. Gill. The effect of plate design, bridging span, and fracture healing on the performance of high tibial osteotomy plates: An experimental and finite element study. Bone Joint Res 2018;7:639-649. DOI: 10.1302/2046-3758.712.BJR-2018-0035.R1.

4.
Mol Cell Biol ; 8(1): 433-40, 1988 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-3336363

RESUMO

We have isolated a cDNA clone from a human skeletal muscle library which contains the complete protein-coding sequence of a skeletal muscle alpha-tropomyosin. This cDNA sequence defines a fourth human tropomyosin gene, the hTM alpha gene, which is distinct from the hTMnm gene encoding a closely related isoform of skeletal muscle alpha-tropomyosin. In cultured human fibroblasts, the hTM alpha gene encodes both skeletal-muscle- and smooth-muscle-type alpha-tropomyosins by using an alternative mRNA-splicing mechanism.


Assuntos
Músculos/fisiologia , Tropomiosina/genética , Sequência de Aminoácidos , Sequência de Bases , Clonagem Molecular , Fibroblastos/fisiologia , Regulação da Expressão Gênica , Genes , Humanos , Dados de Sequência Molecular , Splicing de RNA , RNA Mensageiro/genética , Distribuição Tecidual
5.
Bone Joint Res ; 5(8): 338-46, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27496914

RESUMO

OBJECTIVES: Modular junctions are ubiquitous in contemporary hip arthroplasty. The head-trunnion junction is implicated in the failure of large diameter metal-on-metal (MoM) hips which are the currently the topic of one the largest legal actions in the history of orthopaedics (estimated costs are stated to exceed $4 billion). Several factors are known to influence the strength of these press-fit modular connections. However, the influence of different head sizes has not previously been investigated. The aim of the study was to establish whether the choice of head size influences the initial strength of the trunnion-head connection. MATERIALS AND METHODS: Ti-6Al-4V trunnions (n = 60) and two different sizes of cobalt-chromium (Co-Cr) heads (28 mm and 36 mm; 30 of each size) were used in the study. Three different levels of assembly force were considered: 4 kN; 5 kN; and 6 kN (n = 10 each). The strength of the press-fit connection was subsequently evaluated by measuring the pull-off force required to break the connection. The statistical differences in pull-off force were examined using a Kruskal-Wallis test and two-sample Mann-Whitney U test. Finite element and analytical models were developed to understand the reasons for the experimentally observed differences. RESULTS: 36 mm diameter heads had significantly lower pull-off forces than 28 mm heads when impacted at 4 kN and 5 kN (p < 0.001; p < 0.001), but not at 6 kN (p = 0.21). Mean pull-off forces at 4 kN and 5 kN impaction forces were approximately 20% larger for 28 mm heads compared with 36 mm heads. Finite element and analytical models demonstrate that the differences in pull-off strength can be explained by differences in structural rigidity and the resulting interface pressures. CONCLUSION: This is the first study to show that 36 mm Co-Cr heads have up to 20% lower pull-off connection strength compared with 28 mm heads for equivalent assembly forces. This effect is likely to play a role in the high failure rates of large diameter MoM hips.Cite this article: A. R. MacLeod, N. P. T. Sullivan, M. R. Whitehouse, H. S. Gill. Large-diameter total hip arthroplasty modular heads require greater assembly forces for initial stability. Bone Joint Res 2016;5:338-346. DOI: 10.1302/2046-3758.58.BJR-2016-0044.R1.

6.
Oncogene ; 35(21): 2723-34, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26387544

RESUMO

Multiple myeloma (MM) remains an incurable malignancy due, in part, to the influence of the bone marrow microenvironment on survival and drug response. Identification of microenvironment-specific survival signaling determinants is critical for the rational design of therapy and elimination of MM. Previously, we have shown that collaborative signaling between ß1 integrin-mediated adhesion to fibronectin and interleukin-6 confers a more malignant phenotype via amplification of signal transducer and activator of transcription 3 (STAT3) activation. Further characterization of the events modulated under these conditions with quantitative phosphotyrosine profiling identified 193 differentially phosphorylated peptides. Seventy-seven phosphorylations were upregulated upon adhesion, including PYK2/FAK2, Paxillin, CASL and p130CAS consistent with focal adhesion (FA) formation. We hypothesized that the collaborative signaling between ß1 integrin and gp130 (IL-6 beta receptor, IL-6 signal transducer) was mediated by FA formation and proline-rich tyrosine kinase 2 (PYK2) activity. Both pharmacological and molecular targeting of PYK2 attenuated the amplification of STAT3 phosphorylation under co-stimulatory conditions. Co-culture of MM cells with patient bone marrow stromal cells (BMSC) showed similar ß1 integrin-specific enhancement of PYK2 and STAT3 signaling. Molecular and pharmacological targeting of PYK2 specifically induced cell death and reduced clonogenic growth in BMSC-adherent myeloma cell lines, aldehyde dehydrogenase-positive MM cancer stem cells and patient specimens. Finally, PYK2 inhibition similarly attenuated MM progression in vivo. These data identify a novel PYK2-mediated survival pathway in MM cells and MM cancer stem cells within the context of microenvironmental cues, providing preclinical support for the use of the clinical stage FAK/PYK2 inhibitors for treatment of MM, especially in a minimal residual disease setting.


Assuntos
Quinase 2 de Adesão Focal/metabolismo , Mieloma Múltiplo/patologia , Animais , Morte Celular/fisiologia , Linhagem Celular Tumoral , Feminino , Quinase 2 de Adesão Focal/antagonistas & inibidores , Humanos , Interleucina-6/metabolismo , Janus Quinase 1/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Microambiente Tumoral
7.
Oncogene ; 4(2): 259-62, 1989 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-2927948

RESUMO

We have constructed a derivative of the trk oncogene in which the cytoskeletal tropomyosin sequences are replaced with skeletal muscle alpha-tropomyosin sequences derived from the same tropomyosin gene by alternative splicing. The biochemical and biological properties of this derivative are indistinguishable from those of the naturally occurring trk oncogene. Thus activation of the oncogenic activity of trk is a function of structural features of tropomyosin which are common to both skeletal muscle and non-muscle isoforms.


Assuntos
Músculos/análise , Oncogenes , Splicing de RNA , Tropomiosina/genética , Animais , Citoesqueleto/análise , Humanos , Camundongos , Fosforilação , Transfecção , Tropomiosina/análise
8.
J Mol Biol ; 164(1): 159-74, 1983 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-6842592

RESUMO

The cytoskeletal extracts of cultured human fibroblasts were found to contain at least four distinct polypeptides, each of which demonstrated the resistance to denaturation and the acidic isoelectric point characteristic of tropomyosin. One of these, hscp 36 (heat-stable cytoskeletal protein having an apparent molecular weight of 36,000), cross-reacted efficiently with an antiserum to chicken skeletal muscle tropomyosin. Furthermore, the messenger RNA coding for hscp 36 was selected by a chicken complementary DNA clone containing a tropomyosin sequence. The abundance of mRNA coding for hscp 36 was found to be similar in both normal and simian virus 40 (SV40) transformed human fibroblasts. The apparent molecular weight of hscp 36 is different from non-muscle tropomyosins previously isolated from human sources, which show the apparent molecular weight of 30,000 normally associated with non-muscle tropomyosin. This, together with the complexity of the heat-stable cytoskeletal proteins present in human fibroblasts, suggests the existence of multiple genes coding for human non-muscle tropomyosins.


Assuntos
Fibroblastos/análise , Tropomiosina , Sequência de Bases , Transformação Celular Neoplásica , Transformação Celular Viral , Células Cultivadas , Reações Cruzadas , Eletroforese em Gel de Poliacrilamida , Temperatura Alta , Humanos , Soros Imunes/imunologia , Peso Molecular , Hibridização de Ácido Nucleico , Biossíntese de Proteínas , RNA Mensageiro , Tropomiosina/genética , Tropomiosina/imunologia
9.
J Mol Biol ; 167(3): 523-37, 1983 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-6308263

RESUMO

We have isolated and characterized a human genomic DNA sequence that defines a family of closely related sequences. At least one member of this family expresses a 2.5 X 10(3) base messenger RNA transcript encoding a 30,000 molecular weight tropomyosin in human fibroblasts. The coding sequence of this mRNA but not the non-coding sequence is also related to that of a 1.1 X 10(3) base mRNA encoding a 36,000 molecular weight non-muscle tropomyosin. This demonstrates the existence of at least two functional genes encoding human non-muscle tropomyosins.


Assuntos
Genes , Tropomiosina/genética , Sequência de Aminoácidos , Sequência de Bases , Clonagem Molecular , DNA/genética , Enzimas de Restrição do DNA , Eletroforese em Gel de Ágar , Fibroblastos/análise , Humanos , Peso Molecular , Biossíntese de Proteínas , RNA Mensageiro/genética
10.
J Mol Biol ; 194(1): 1-10, 1987 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-3612796

RESUMO

We have isolated a cDNA that contains the complete coding sequence of a 3.0 X 10(3) base human fibroblast mRNA together with a large part of its 3' untranslated sequence. The deduced protein sequence is very similar if not identical to the sequence of horse platelet tropomyosin, a 247 amino acid protein. In vitro translation of an SP6 transcript of this cDNA reveals that the protein product of the 3.0 X 10(3) base mRNA is TM30p1, one of the five proteins in human fibroblasts that have been shown to possess the physical and chemical characteristics of tropomyosin. This mRNA is encoded by a gene family that consists of a functional gene and multiple RNA-copy pseudogenes. This family of sequences is distinct from the gene family encoding TM30nm, a cytoskeletal tropomyosin very similar in electrophoretic mobility to TM30p1, but which shows significant differences in primary structure.


Assuntos
DNA , Genes , Tropomiosina/genética , Sequência de Bases , Clonagem Molecular , Eletroforese , Éxons , Fibroblastos/análise , Humanos , Biossíntese de Proteínas , RNA Mensageiro/genética , Transcrição Gênica
11.
J Mol Biol ; 201(3): 507-15, 1988 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-3418707

RESUMO

We have isolated clones of human genomic DNA which contain the structural elements of the hTMnm gene. In non-muscle tissue this gene produces a 2.5 kb (1 kb = 10(3) bases or base-pairs) mRNA encoding TM30nm, a 248 amino acid cytoskeletal tropomyosin. In muscle, alternative splicing of this gene results in the expression of a 1.3 kb mRNA encoding a 285 amino acid skeletal muscle alpha-tropomyosin. The hTMnm gene spans at least 42 kb of DNA and consists of 13 exons, only five of which are common to both the 2.5 kb and 1.3 kb transcripts. The boundaries of the exons giving rise to the muscle-specific isoform are identical to the base to those of other genes encoding muscle tropomyosins. A comparison of the structures of exons encoding the amino-terminal sequences of the muscle and non-muscle isoforms suggests that the hTMnm gene has evolved by a specific pattern of exon duplication with alternative splicing.


Assuntos
Evolução Biológica , Genes , Tropomiosina/genética , Sequência de Aminoácidos , Sequência de Bases , DNA , Humanos , Modelos Genéticos , Dados de Sequência Molecular , Músculos/metabolismo , Polimorfismo Genético
12.
Res Vet Sci ; 25(1): 63-6, 1978 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-100838

RESUMO

The long-term effects of colostrum on active immunity to two unrelated antigens are described. Lambs were fed with pooled colostrum--to equalise passive immunity--with or without added antibodies to egg albumin (Ea). There were significant breed differences in the response both to Brucella abortus measured at one month of age, and to Ea, measured at three months of age, although there was no significant correlation between the responses to the two antigens, either within or between breeds. Surprisingly, whereas antibodies to Ea caused a four-fold reduction in antibody production to B abortus, they did not affect the overall mean response to Ea. But the timing of the response to Ea was significantly affected, suggesting that the low persisting concentrations of antibody had caused qualitative changes in the response.


Assuntos
Anticorpos/análise , Brucella abortus/imunologia , Imunidade Ativa , Imunidade Materno-Adquirida , Ovalbumina/imunologia , Ovinos/imunologia , Animais , Anticorpos Antibacterianos/análise , Formação de Anticorpos , Colostro/imunologia , Feminino
13.
Psychol Rep ; 81(3 Pt 1): 723-33, 1997 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9400065

RESUMO

The present investigation sought to distinguish hope from optimism in the context of a 10-wk. prospective study involving reports of health outcomes. Gottschalk's (1985) Hope Scale and Scheier and Carver's (1987) Life Orientation Test which assesses optimism were given to subjects, along with a health questionnaire. Ten weeks later subjects were given a second health questionnaire. To rule out potential confounds we included measures of neuroticism, depression, extroversion, and social desirability. After controlling for the effects of correlated confounds, we found that lower hope scores (but not optimism) were correlated with several dimensions of reported health, including frequency and severity of illness.


Assuntos
Atitude Frente a Saúde , Motivação , Adolescente , Adulto , Feminino , Humanos , Controle Interno-Externo , Masculino , Inventário de Personalidade , Transtornos Somatoformes/psicologia , Estudantes/psicologia
16.
Eur J Biochem ; 126(2): 293-7, 1982 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-7128591

RESUMO

Recombinant plasmids have been isolated which contain sequences complementary to two distinct alpha-tropomyosin mRNA species present in chicken leg muscle. The proteins coded for by these different mRNAs could be distinguished by their electrophoretic behaviour in the presence of 3.5 M urea. The properties of the minor alpha-tropomyosin of chicken leg muscle were similar to those reported for the alpha-tropomyosin of slow twitch chicken skeletal muscle. Sequence analysis of available plasmids showed that the deduced protein sequences of both types of alpha-tropomyosin were very similar and closely related to the known protein sequence of rabbit alpha-tropomyosin. However considerable variation in nucleotide coding sequence of the two alpha-tropomyosin mRNAs was found.


Assuntos
Músculos/metabolismo , RNA Mensageiro/isolamento & purificação , Tropomiosina/isolamento & purificação , Animais , Sequência de Bases , Galinhas , DNA Recombinante , Eletroforese , Biossíntese de Proteínas
17.
Eur J Biochem ; 119(2): 353-8, 1981 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7308190

RESUMO

The expression of the mRNA coding for glyceraldehyde-3-phosphate dehydrogenase has been studied during embryonic development of the chicken. In each tissue examined, only one mRNA species coding for a single glyceraldehyde-3-phosphate dehydrogenase subunit could be detected using translation in vitro with RNA blotting and hybridization. The mRNA species coding for glyceraldehyde-3-phosphate dehydrogenase subunits in different chicken tissues have identical electrophoretic mobilities suggesting that they are structurally very similar if not identical.


Assuntos
Clonagem Molecular , Gliceraldeído-3-Fosfato Desidrogenases/genética , Biossíntese de Proteínas , RNA Mensageiro/genética , Transcrição Gênica , Animais , Sistema Livre de Células , Embrião de Galinha , DNA Recombinante , Peso Molecular , Hibridização de Ácido Nucleico , Plasmídeos , Reticulócitos/metabolismo
18.
Nucleic Acids Res ; 9(12): 2675-89, 1981 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-7279659

RESUMO

Recombinant plasmids have been constructed with contain sequences complementary to the mRNA coding for skeletal muscle alpha-tropomyosin. These recombinants were detected initially using a selective cDNA probe and subsequently using a messenger RNA selection assay. alpha-TM plasmids hybridize to a singly mRNA species smaller than 18S ribosomal RNA and found only in skeletal muscle. Cross-hybridization with mRNA's coding for other tropomyosins could not be detected under normal conditions. However, under conditions of reduced stringency alpha- TM plasmids cross-hydridize with an RNA species in heart muscle which may code for cardiac tropomyosin.


Assuntos
DNA Recombinante/metabolismo , Plasmídeos , RNA Mensageiro/genética , Tropomiosina/genética , Animais , Sequência de Bases , Embrião de Galinha , Clonagem Molecular , Proteínas Musculares/genética , Músculos/metabolismo , Miocárdio/metabolismo , Hibridização de Ácido Nucleico , Biossíntese de Proteínas , Reticulócitos/metabolismo
19.
J Biol Chem ; 270(14): 8037-43, 1995 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-7713905

RESUMO

Many tumor cell lines overexpress DNA methyltransferase (MeTase) activity; however it is still unclear whether this increase in DNA MeTase activity plays a causal role in naturally occurring tumors and cell lines, whether it is critical for the maintenance of transformed phenotypes, and whether inhibition of the DNA MeTase in tumor cells can reverse transformation. To address these basic questions, we transfected a murine adrenocortical tumor cell line Y1 with a chimeric construct expressing 600 base pairs from the 5' of the DNA MeTase cDNA in the antisense orientation. The antisense transfectants show DNA demethylation, distinct morphological alterations, are inhibited in their ability to grow in an anchorage-independent manner, and exhibit decreased tumorigenicity in syngeneic mice. Ex vivo, cells expressing the antisense construct show increased serum requirements, decreased rate of growth, and induction of an apoptotic death program upon serum deprivation. 5-Azadeoxycytidine-treated cells exhibit a similar dose-dependent reversal of the transformed phenotype. These results support the hypothesis that the DNA MeTase is actively involved in oncogenic transformation.


Assuntos
Metilases de Modificação do DNA/fisiologia , DNA/metabolismo , Neoplasias Experimentais/metabolismo , RNA Antissenso/biossíntese , RNA Mensageiro/genética , Animais , Sequência de Bases , Divisão Celular , Células Cultivadas , Metilases de Modificação do DNA/genética , Masculino , Metilação , Camundongos , Dados de Sequência Molecular , Neoplasias Experimentais/genética , RNA Mensageiro/antagonistas & inibidores , Transfecção , Células Tumorais Cultivadas
20.
Nature ; 322(6080): 648-50, 1986.
Artigo em Inglês | MEDLINE | ID: mdl-3018581

RESUMO

The trk oncogene is a human transforming gene generated by the fusion of tropomyosin gene sequence to a truncated tyrosine kinase receptor gene. We have now characterized the normal tropomyosin gene from which the trk oncogene is derived. At least two different transcripts are expressed by this gene using a tissue-specific alternative messenger RNA splicing mechanism: a 2.5-kilobase (kb) mRNA encoding a 248-amino-acid tropomyosin in human fibroblasts and a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human skeletal muscle. The rearrangement which generates the trk oncogene preserves most of the tropomyosin-coding sequences of the normal gene, including exons alternatively spliced in muscle and non-muscle tissue. We therefore expect the trk oncogene to show a tissue-specific pattern of transforming activity. Correct expression of the trk oncogene can occur only in non-muscle tissues. In muscle tissue the oncogene would almost certainly be inactive, as splicing according to the alternative muscle pattern aborts synthesis of the tyrosine kinase domain.


Assuntos
Oncogenes , Receptores de Superfície Celular/genética , Tropomiosina/genética , Sequência de Bases , Fibroblastos/análise , Genes , Genes Sintéticos , Humanos , Músculos/análise , Splicing de RNA , Homologia de Sequência do Ácido Nucleico , Tropomiosina/biossíntese
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