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C J Dawe

Publications and source records attributed to C J Dawe.

At least 19 recordsLinked to original sources
PubMed1992

Heterogeneity in state and expression of viral DNA in polyoma virus-induced tumors of the mouse.

We have examined the state and expression of polyoma viral DNA in representative epithelial and mesenchymal tumors, using a combination of biochemical and in situ methods. Results showed wide variations among tumor types and also in different regions within individual tumors, with respect to copy number of viral DNA, presence or absence of deletions, and expression of early and late viral proteins. Epithelial tumors showed the greatest heterogeneity. High copy free viral DNA, frequently with deletions, was found in all such tumors. A portion of free viral DNA was recoverable as transcriptionally active minichromosomes. Three distinct subpopulations of cells were distinguished by in situ analyses. Type 1 cells showed high copy free viral DNA and expressed the major viral capsid protein VP1; these cells appeared to be at various stages of productive (lytic) viral infection. Some productively infected cells were able to undergo mitosis; in a portion of these cells, VP1 was found in close association with the mitotic spindle. Type 2 cells contained high copy free DNA but did not express VP1; by some unknown mechanism, these cells manifest a post-replication block to late gene expression and lytic infection. Type 3 cells contained only low copy, presumably integrated, viral DNA and expressed no VP1; they thus resemble cells transformed in vitro by the virus. Epithelial tumors contained variable mixtures of these subpopulations, while mesenchymal tumors were composed of Type 3 cells only. Differences in virus-cell interactions are discussed in terms of their possible implications in tumor development.

Animals↗
PubMed1992

Changes in frequency, morphology, and behavior of tumors induced in mice by a polyoma virus mutant with a specifically altered oncogene.

Alterations in the tumor-inducing ability of a polyoma virus mutant encoding a partially defective middle T oncogene have been investigated. The mutant middle T associates with and activates the tyrosine protein kinase pp60c-src normally but does not promote binding of a second enzyme, phosphatidyl-inositol 3-kinase. Compared with the wild type virus, this mutant shows an altered and reduced ability to induce tumors after inoculation into newborn mice, as judged by the following criteria: lower frequency of tumors, reduced morbidity and increased survival times of host mice, changes in the spectrum of tumor types, and altered morphologic properties of tumors at several target organ sites. These results indicate an important role of changes in 3-phosphoinositide metabolism in induction of a variety of tumors in this experimental system.

Animals↗
PubMed1991

Polyomavirus tumor induction in mice: effects of polymorphisms of VP1 and large T antigen.

By testing recombinants between "high tumor" (inducing a high incidence of tumors) and "low tumor" (inducing a low incidence of tumors) strains of polyomavirus, we have previously shown that the key determinant(s) for induction of a high tumor profile resides in coding regions of the high tumor strain (R. Freund, G. Mandel, G. G. Carmichael, J. P. Barncastle, C. J. Dawe, and T. L. Benjamin, J. Virol. 61:2232-2239, 1987). Three single-amino-acid differences between the PTA (high tumor) and RA (low tumor) virus strains have now been identified by DNA sequencing, one each in the large T antigen, in the region common to the middle and small T antigens, and in the major capsid protein VP1. Further tests of appropriate recombinants and oligonucleotide-induced mutants show that VP1 of PTA is the major determinant for induction of a high tumor profile, including all tumors of epithelial origin. The differential effect of the VP1s of PTA and RA on the tumor profile is discussed in terms of a likely contribution of the polymorphic region of VP1 to binding of receptors and infection of different cell types in the animal. The polymorphism in the large T antigen has a more restricted action, which is seen only when tested in virus carrying the VP1 type of PTA; the PTA large T antigen then promotes more rapid growth of tumors of salivary gland and thymus than the RA large T antigen.

Antigens, Polyomavirus Transforming↗
PubMed1991

Polyomavirus replication in mice: influences of VP1 type and route of inoculation.

Patterns of polyomavirus replication and spread have been studied following inoculation of virus into newborn mice. Levels of virus replication in different tissues were followed in situ by using whole mouse section blots and immunoperoxidase staining for the major capsid protein VP1, as well as by tissue extraction and direct quantitation of viral DNA and infectious virus. Patterns of replication and spread were compared between the "high tumor" strain (inducing a high incidence of tumors) PTA and and the "low tumor" strain (inducing a low incidence of tumors) RA, following different routes of inoculation. The ability to induce a high tumor profile correlated with the ability to establish disseminated productive infection, with the kidney as a major site of amplification. Furthermore, results with PTA-RA recombinant viruses and site-directed mutants showed that the VP1 specificity of PTA, demonstrated earlier to be a critical determinant for induction of a high tumor profile (R. Freund, A. Calderone, C. J. Dawe, and T. L. Benjamin, J. Virol. 65:335-341, 1991), is also critical for amplification in the kidney and for establishment of disseminated infections.

Animals↗
PubMed1990

T-cell lymphomas emerging as epineoplasms in mice bearing transplanted polyoma virus-induced salivary gland tumors.

A subset of salivary epithelial tumors induced by mouse polyoma virus (PyV) has been designated lymphoepithelioma on the basis of a prominent lymphocytic component. Serial transplantation of this variant has previously been observed to result in lymphoma development. A recent repetition of this phenomenon allowed us to characterize the lymphoma cell populations with regard to phenotypic markers and PyV content. Lymphomas emerged in recipients of the third, fifth, sixth, and seventh transplant generations of the lymphoepithelioma. Most lymphomas were widely disseminated in hematopoietic and lymphoreticular tissues, and other sites as well. Flow cytometric analysis of lymphocyte populations from lymphomas in six recipients revealed that, while all lymphomas expressed phenotypic markers of immature cortical thymocytes, i.e., Thy-1, Pgp-1, Jlld, and CD5, they were not uniform with regard to other T-cell markers, notably CD4 and CD8. Varying levels of T-cell receptor markers CD3 and alpha/beta, as well as interleukin 2 receptor, were also noted. DNA blot analysis failed to detect PyV in lymphoma cells at a sensitivity level capable of detecting less than one intact copy per cell. It appears improbable the lymphoma was directly induced by PyV. Hypotheses invoking other mechanisms of lymphoma development are outlined.

Animals↗
PubMed1990

Implications of aquatic animal health for human health.

Human health and aquatic animal health are organically related at three distinct interfaces. Aquatic animals serve as important contributors to the nutritional protein, lipid, and vitamin requirements of humans; as carriers and transmitters of many infectious and parasitic diseases to which humans are susceptible; and as indicators of toxic and carcinogenic substances that they can convey, in some part, from aquatic environments to man and other terrestrial animals. Transcending these relationships, but less visible and definable to many, is the role that aquatic animals play in the sustenance of our integrated planetary ecosystem. Up to the present, this ecosystem has been compatible with mankind's occupation of a niche within it at high but ultimately limited population levels. In the past century we have become clearly aware that human activities, particularly over-harvesting of aquatic animals together with chemical degradation of their habitats, can quite rapidly lead to perturbances that drastically shift aquatic ecosystems toward conditions of low productivity and impaired function as one of earth's vital organs. The negative values of aquatic animals as disease vectors are far outweighed by their positive values as nutritional sources and as sustainers of a relatively stable equilibrium in the global ecosystem. In the immediate future we can expect to see increased and improved monitoring of aquatic habitats to determine the extent to which aquatic animals cycle anthropogenic toxic and carcinogenic chemicals back to human consumers. In the long term, methods are particularly needed to assess the effects of these pollutants on reproductive success in aquatic communities and in human communities as well. As inputs of habitat-degrading substances change in quality and quantity, it becomes increasingly urgent to evaluate the consequences in advance, not in retrospect. A new, more realistic and comprehensive philosophy regarding aquatic environmental preservation and equally new and comprehensive technological advances reflective of this philosophy will be required. In the next century we will see a serious test of whether or not mankind has lost its ability to foresee and forestall the side effects of scientific and technological ingenuity.

Animals↗
PubMed1989

Phosphorylation of middle T by pp60c-src: a switch for binding of phosphatidylinositol 3-kinase and optimal tumorigenesis.

Substitution of phenylalanine for tyrosine 315 of the polyoma virus middle T (mT) protein lowers the incidence and limits the spectrum of tumors induced following inoculation of the virus into newborn mice. This substitution removes the major site of phosphorylation by pp60c-src without altering the ability of mT to associate with or to activate pp60c-src. The mutant mT fails to show binding of a phosphatidylinositol 3-kinase (Ptdlns 3-kinase) activity that is normally present in wild-type mT complexes. Furthermore, an anti-peptide antiserum that specifically recognizes mT lacking phosphate at tyrosine 315 precipitates binary (mT-pp60c-src) but not ternary (mT-pp60c-src-Ptdlns 3-kinase) complexes from wild-type infected cell extracts. Reprecipitation with either anti-pp60c-src or anti-mT serum brings down ternary complexes containing mT phosphorylated on tyrosine 315. Phosphorylation of mT by pp60c-src in vivo is therefore a critical event for binding of Ptdlns 3-kinase and for expression of the full tumorigenic potential of the virus.

Amino Acid Sequence↗
PubMed1988

Duplication of noncoding sequences in polyomavirus specifically augments the development of thymic tumors in mice.

A 40-base-pair duplication of noncoding sequences in polyomavirus specifically augmented the development of thymic epitheliomas following inoculation of virus into newborn mice. Virus strains carrying only one copy of this sequence induced a full spectrum of tumors except for overt thymic tumors. This 40-base-pair repeat, on the early side of the replication origin, constituted a tissue-specific regulatory determinant for tumor induction.

Animals↗
PubMed1988

The middle T proteins of high and low tumor strains of polyomavirus function equivalently in tumor induction.

The PTA strain of polyomavirus induces a variety of epithelial as well as mesenchymal tumors at high frequencies, while the RA strain induces only rare mesenchymal tumors following inoculation into newborn mice. DNA sequence analysis has revealed one amino acid difference between the middle T (mT) proteins encoded by these two virus strains. To test for possible biological differences between the mT proteins we constructed a recombinant virus carrying mT-coding sequences of RA on a PTA background. The tumor profile induced by this recombinant is like that of PTA, demonstrating that the transforming protein of the low tumor strain is competent to induce a high tumor profile. We conclude that a structural determinant(s) outside of mT in the PTA virus strain is important in induction of a broad spectrum of tumors and particularly those of epithelial origin.

Animals↗
PubMed1987

Polyomavirus tumor induction in mice: influences of viral coding and noncoding sequences on tumor profiles.

We determined the DNA sequences of the noncoding regions of two polyomavirus strains that differ profoundly in their abilities to induce tumors in mice. Differences between strains were found, both on the late side of the replication origin in the region containing known enhancer elements and on the early side of the origin, affecting the number and location of large-T-antigen-binding sites. By constructing and analyzing recombinant viruses between these high- and low-tumor strains, we attempted to localize determinants which affect the frequency and histotype of tumors. Seven recombinants were constructed and propagated in vitro, and the tumor profile of each was established by inoculation into newborn C3H mice. Recombinants containing noncoding sequences from the high-tumor strain and coding sequences from the low-tumor strain behaved like the latter, inducing tumors at a low frequency and strictly of mesenchymal origin. Reciprocal recombinants with noncoding sequences of the low-tumor strain linked to structural determinants from the high-tumor strain induced several types of epithelial tumors typical of the high-tumor strain but at reduced frequency, in addition to mesenchymal tumors. A high frequency and full diversity of epithelial tumors required, in addition to structural regions from the high-tumor strain, noncoding sequences on the early side of the origin also present in this strain. A high-tumor profile thus resulted from the combined effects of structural and regulatory determinants in the high-tumor strain, with the former affecting primarily the tissue tropism and the latter affecting the frequency of tumors. No differential effects of the enhancer regions from the late side of the origin in the two virus strains were seen in this study.

Animals↗
PubMed1987

Oncozoons and the search for carcinogen-indicator fishes.

This essay attempts to bring into perspective the importance of hereditary as well as environmental factors as potential causes of neoplasms in feral fishes. Concepts delineated by Knudson regarding hereditary cancers in man and experimental animals will probably be found operative in certain demographic units (oncozoons) among feral fishes bearing neoplasms. Hereditary factors include: antioncogenes (regulatory genes), which act as suppressors of neoplastic expression in homozygous, heterozygous, or hemizygous states, as well as constitutional (structural) genes that influence carcinogen activation or deactivation through enzyme gene products, genes that influence immunologic responses, and gene abnormalities that favor spontaneous or induced mutations. The two major classes of genes (oncogenes and antioncogenes) that influence the manifestation of cancers appear to operate through different mechanisms, but conceivable interactions have not been widely investigated, especially in tumor enzootics among feral fishes. Some explorations have been undertaken in the laboratory by Anders and collaborators in studies of suppressor genes (antioncogenes) and the cellular sarc gene (an oncogene) in melanophoromas in platyfish-swordtail hybrids and backcrosses. Some feral fish oncozoons that exhibit features of hereditary oncodemes as seen in man have been tentatively identified here as candidate systems to be studied more intensively in laboratories, particularly using cytogenetic analysis and breeding methods. In the search for carcinogen-indicator fish species in feral habitats, the traditional approach has been to survey fish populations with the aim of first finding enzootics of fish neoplasia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Variations in polyoma virus genotype in relation to tumor induction in mice. Characterization of wild type strains with widely differing tumor profiles.

The authors have explored the effects of variations in mouse polyoma virus genotype on patterns of tumor formation in the mouse. Four "wild type" virus strains were surveyed. Two were highly oncogenic, inducing multiple tumors of epithelial and mesenchymal origin, at high frequency and with short latency. The other two strains were weakly oncogenic, inducing fewer tumors, solely of mesenchymal origin, and after a long latency. These sharply contrasting tumor profiles were reproduced with virus stocks derived from molecularly cloned viral genomes. Though vastly different in their oncogenic properties, these cloned viruses proved equally effective in transforming established rat fibroblasts in culture and showed the same patterns of tumor antigen expression in cultured mouse cells. Complexes of polyoma middle T antigen and pp60c-src were demonstrated in extracts of epithelial tumors induced by a highly oncogenic virus strain. It is concluded that polyoma viral genetic determinants for tumor induction in the mouse are more complex than those previously defined by the use of cell transformation systems.

Animals↗
PubMed1987

Necrotizing arterial lesions in mice-bearing tumors induced by polyoma virus.

In the course of determining tumor profiles for wild-type and recombinant mouse polyoma viruses (MPyV's), we fortuitously discovered two types of necrotizing arterial disease in polyoma tumor-bearing C3H/BiDa mice. One type, designated BLAND, consisted of foci of necrosis unaccompanied by inflammatory reaction, in the muscular coat of aorta, pulmonary arterial trunk, and primary or occasionally secondary branches of these vessels. BLAND lesions contained MPyV capsid antigen VP1 as shown by immunocytochemistry, and appeared to be the result of viral cytolytic infection within artery walls. Lesions of the second type are designated PANoid in view of their resemblance to polyarteritis nodosa in humans. PANoid lesions had much the same distribution in the arterial tree as BLAND lesions and were also focal, but had the histologic properties of highly destructive acute inflammatory reactions. Specifically, there were dense infiltrations of polymorphonuclear leukocytes in any and often all coats of the arterial wall, acute fibrinoid necrosis, endothelial proliferations, intravascular thrombosis, and in one example, rupture of the intimal and medial coats with microaneurysm formation. In the acute phase, PANoid lesions exhibited attenuation, fragmentation, and loss of elastic laminae, and in the healing phase, intimal and medial fibrosis with varying degrees of lumenal occlusion. PANoid lesions gave negative immunocytochemical reactions for MPyV capsid antigen VP1, indicating either that the antigen was not present, or that it was masked in complexes with antibody and C3. BLAND lesions were found in 51% of 459 MPyV-infected mice, while PANoid lesions were found in 11%. There was no sex predilection for either type lesion, and practically all mice with lesions fell within ages 60-200 days. We suspect the PANoid lesions are examples of immune-complex arteritis related to persistent MPyV infection, but support for this hypothesis is presently tenuous, resting entirely on the coexistence of BLAND and PANoid lesions in MPyV-infected mice and the histological resemblance of PANoid lesions to naturally occurring and experimentally induced immune complex arteritis.

Animals↗
PubMed1985

A determinant of polyomavirus virulence enhances virus growth in cells of renal origin.

We have identified a strain of polyomavirus, Py(L), which is unusual in causing acute morbidity and early death after inoculation of newborn mice. We determined that these animals died of kidney failure associated with extensive, virus-mediated destruction of renal tissue. Interestingly, the Py(L) strain infects baby mouse kidney cell cultures more efficiently than do other strains.

Aging↗
PubMed1979

Microcinematographic demonstration of synchronous and asynchronous myoepithelial contractions in mouse submandibular gland rudiments in organotypic culture.

Time-lapse phase-contrast cinematography revealed contractile activity within mouse submandibular salivary gland rudiments in organotypic culture. Three types of contraction were distinguishable. In type I (voiding contractions), all portions of the gland contracted synchronously, and the active state ranged from 30 min to 2 hr. In type II (priming contractions), all portions of the gland contracted synchronously, but the active state was shorter, ranging from 4 to 10 min. In type III (churning contractions), isolated foci in lobules or secretory units throughout the gland contracted asynchronously and had very short active states of about 1 min. By electron microscopy, myoepithelial cells could first be demonstrated in submandibular glands developing either in vitro or in vivo, at 21 days postconception. Contractions in the cultured rudiments began as early as 18 days postconception. Since neither smooth nor striated muscle could be identified in these glands by electron microscopy, the contractions are believed to result from myoepithelial activity that apparently may begin before ultrastructural evidence of myoepithelial differentiation is clearly present. Although, for over a century, myoepithelium has been presumed to have a contractile function and indirect evidence has lent ample support to this presumption, the present study represents the first direct cinematographic demonstration and characterization of myoepithelial contractions, under conditions in vitro.

Animals↗
PubMed1979

Capacity of mammary fat pads of adult C3H/HeMs mice to interact morphogenetically with fetal mammary epithelium.

When rudimentary mammary epithelium from 13- to 17-day female C3H/HeMs fetuses was transplanted into gland-free mammary fat pads of 3-week-old mice, organogenetic development of the grafts occurred, resembling that seen in normal mammary gland morphogenesis. Initial developmental growth did not require the reproductive hormones. Mammary fat pads of juvenile (3-wk-old), young adult (8- to 12-wk-old), and fully matured (40-wk-old) females had equal ability to interact morphogenetically with fetal mammary epithelium. Fetal pulmonary, pancreatic, and salivary gland epithella showed no morphogenetic response within adult mammary fat. An exception was rudimentary hair follicle epithellum, which underwent extensive development toward hair follicles within mammary fat. Mammary glands that developed from rudimentary mammary epithellum transplanted into gland-free fat pads underwent morphologic changes characteristic of lactation when the hosts bore young.

Animals↗