Biomedical subjects

E R Cameron

Publications and source records attributed to E R Cameron.

7 recordsLinked to original sources

PubMed1997

Recent advances in transgenic technology.

Techniques that allow modification of the mammalian genome have made a considerable contribution to many areas of biological science. Despite these achievements, challenges remain in two principal areas of transgenic technology, namely gene regulation and efficient transgenic livestock production. Obtaining reliable and sophisticated expression that rivals that of endogenous genes is frequently problematic. Transgenic science has played an important part in increasing understanding of the complex processes that underlie gene regulation, and this in turn has assisted in the design of transgene constructs expressed in a tightly regulated and faithful manner. The production of transgenic livestock is an inefficient process compared to that of laboratory models, and the lack of totipotential embryonic stem (ES) cell lines in farm animal species hampers the development of this area of work. This article highlights recent progress in efficient trans gene expression systems, and the current efforts being made to find alternative means of generating transgenic livestock.

Animals↗

PubMed1997

p53 and tumour viruses: catching the guardian off-guard.

Oncogenic viruses have evolved direct and indirect mechanisms to overcome the tumour suppressor p53. Fortunately, tumour development is limited by the narrow cell tropisms of the viruses concerned and the host immune response. However, such viruses are helping to elucidate the p53 response pathway and may play a future role as novel cancer therapeutic agents.

Animals↗

PubMed1997

Skewed T-cell receptor Vbeta8.2 expression in transgenic CD2-myc induced thymic lymphoma: a role for antigen stimulation in tumour development?

Transgenic mice expressing the c-myc proto-oncogene under the control of the CD2-dominant control region show stochastic development of mainly clonal thymic lymphoma with long latency, indicating that cooperative events are needed for the development of the fully malignant phenotype. Previous studies have suggested that T-cell receptor-associated signals can contribute to tumour development. We have therefore used this transgenic model of T-cell transformation to determine whether antigen-specific responses could constitute an epigenetic event in lymphomagenesis. The T-cell receptor (TcR) repertoires of lymphoma clones were analysed with a panel of monoclonal antibodies (Abs) recognizing TcR Vbeta chains. The Vbeta repertoire of tumour clones arising in these mice was non-random with overrepresentation of Vbeta8.2 TcR species. The majority of Vbeta8.2+ clones were of a mature CD3+ CD8 single-positive (SP) phenotype. The biased TcR usage, together with a mature cell phenotype is consistent with the hypothesis that TcR-mediated signals cooperate with activated myc during T-cell transformation.

Animals↗

PubMed1996

Apparent bypass of negative selection in CD8+ tumours in CD2-myc transgenic mice.

A role for antigen stimulation in lymphoid neoplasia has been postulated and is supported by indirect evidence that suggests that the interaction of antigen with both T cells and B cells may constitute an epigenetic event that can contribute to tumour induction or tumour progression. Using myc-bearing transgenic mice that develop mainly clonal T-cell lymphomas we have investigated the possibility that endogenous antigen-mediated clonal deletion might be overridden in tumorigenesis. CD2-myc transgenic mice were backcrossed on to a CBA/Ca background to ensure Mtv-mediated deletion of V beta 11-expressing T cells in the resultant offspring. Lymphomas arising from these mice were subsequently screened for V beta 11 expression. There was a clear correlation between the age at which mice developed neoplasia and the tumour phenotype. Mice with CD4- CD8+ tumours succumbed to thymic lymphoma at a significantly younger age than mice developing CD4+ CD8+ tumours. A small number of tumours consisted of the 'forbidden' V beta 11 phenotype, showing that cells vulnerable to transformation could escape negative selection. The majority of the V beta 11-positive tumours were CD4- CD8+ and were only observed in mice showing clinical evidence of tumour development at a relatively young age. The phenotype of these cells and the age at which tumours arose suggests that T cells escaping tolerance may be susceptible to transformation.

Animals↗

PubMed1996

Moloney murine leukemia virus-induced lymphomas in p53-deficient mice: overlapping pathways in tumor development?

The effect of Moloney murine leukemia virus (MoMLV) infection was examined in mice lacking a functional p53 gene. Virus-infected p53-/- mice developed tumors significantly faster than uninfected p53-/- or virus-infected p53+/+ littermates. However, the degree of synergy between MoMLV and the p53 null genotype was weaker than the synergy between either of these and c-myc transgenes. A similar range of T-cell tumor phenotypes was represented in all p53 genotype groups, including p53-/- mice, which developed thymic lymphomas as the most common of several neoplastic diseases. Lack of p53 was associated with higher rates of metastasis and the ready establishment of tumors in tissue culture. Loss of the wild-type allele was a common feature of tumors in p53+/- mice and was complete in tumor cells in vitro, but this appeared to occur by a mechanism other than proviral insertion at the wild-type allele. A lower average MoMLV proviral copy number was observed in tumors of the p53 null and heterozygote groups, suggesting that the absence of a functional p53 gene reduced the number of steps required to complete the malignant phenotype. Mink cell focus-forming virus-like proviruses were detected in tumors of all infected mice but were relatively rare in p53 null mice. Analysis of c-myc, pim-1, and pal-1 showed that these loci were occupied by proviruses in some cases but at similar frequencies in p53 wild-type and null mice. In conclusion, while inactivation of p53 in the germ line predisposes mice to tumors similar in phenotype to those induced by MoMLV, it appears that virus-induced tumors generally occur without p53 loss. We speculate that a bcl-2-like function carried or induced by MoMLV may underlie this p53-independent pathway.

Alleles↗

PubMed1995

Synergy between a human c-myc transgene and p53 null genotype in murine thymic lymphomas: contrasting effects of homozygous and heterozygous p53 loss.

Activation of the c-myc oncogene and functional loss of the p53 tumour suppressor gene are among the most frequently recorded genetic lesions in neoplasia but their combined effect has not previously been investigated. By breeding together mice transgenic for human c-myc (CD2-myc) and mice carrying an inactive p53 allele (p53-/-) we found that these genetic lesions act synergistically in vivo. Offspring carrying the CD2-myc transgene and the homozygous p53 null mutation (p53-/-/CD2-myc) were viable but developed thymic lymphomas with dramatically increased frequency and reduced latency compared to both parental groups. The tumour phenotype was similar to that previously recorded for CD2-myc mice (predominantly CD3+, CD4+8+) but tumour clonal complexity and metastasis was significantly greater in the p53-/-/CD2-myc mice. In contrast, no significant increase in tumour incidence was seen in p53+/-/CD2-myc vs p53+/+/CD2-myc mice over a 6 month observation period. However, the loss of wild type p53 in a proportion of tumour cells in p53+/-/CD2-myc lymphomas suggests that wild type allele loss can occur as a late progression step rather than an initiating step in these tumours. We suggest that p53 loss of function may collaborate with the CD2-myc transgene at more than one stage in thymic lymphoma development.

Animals↗

PubMedDate not supplied

Transgenic science.

The ability to manipulate the genome of the whole animal has, for the past 10 years, provided researchers with an alternative route of inquiry into many complex biological processes. Transgenic animals have numerous applications, encompassing a wide range of different disciplines, but they have proved especially useful in the investigation of gene regulation and gene function within the context of the living animal. This review describes the different techniques which have been used to produce transgenic animals and highlights advances which have been achieved using the transgenic approach.

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