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J M Angel

Publications and source records attributed to J M Angel.

At least 19 recordsLinked to original sources
PubMed2001

Confirmation of the mapping of a 12-O-tetradecanoylphorbol-13-acetate promotion susceptibility locus, Psl1, to distal mouse chromosome 9.

Susceptibility to two-stage skin carcinogenesis in the mouse is affected by several genes. In addition, studies suggest that genes that modify the response of mice to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) also may influence histologic changes in the skin as the result of TPA treatment. One TPA susceptibility locus, Psl1, previously was mapped to distal chromosome 9. The mapping of this locus was confirmed by marker-based genotypic selection. Furthermore, Psl1 or a gene closely linked to Psl1 influenced epidermal hyperplasia and epidermal labeling index of mice treated with TPA.

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PubMed2000

A locus that influences susceptibility to 1, 2-dimethylhydrazine-induced colon tumors maps to the distal end of mouse chromosome 3.

While inheritance of mutated alleles of highly penetrant tumor suppressor genes such as retinoblastoma or p53 predisposes individuals to a greatly increased risk of developing cancer, epidemiological data indicate that the majority of sporadic tumors in humans result from interactions of environmental and host genetic factors. The host genetic factors are poorly penetrant tumor susceptibility genes that determine the likelihood that a cancer will arise from carcinogen exposure. The majority of colon tumors in humans are sporadic in nature. 1,2-dimethylhydrazine (DMH)-induced colon tumors in mice provide a useful animal model to identify genes that influence susceptibility to carcinogen-induced colon tumors in humans. A genome-wide scan of genetic crosses of relatively sensitive C57BL/6J with relatively resistant CBA mice treated with DMH revealed a linkage of DMH susceptibility with the distal end of mouse chromosome 3, suggesting that one or more tumor susceptibility genes may map to this region.

1,2-Dimethylhydrazine↗
PubMed1999

Genetics of skin tumor promotion.

Cancer development is a multistep process that involves both the activation of protooncogenes and the inactivation of tumor suppressor genes. Furthermore, both epidemiological and experimental data indicate that a third class of genes, tumor susceptibility genes, control the propensity to develop carcinogen-induced tumors. Recent studies suggest that tumor susceptibility is determined by the combined effect of both sensitivity and resistance genes. The mouse skin model of multistage carcinogenesis is an excellent paradigm in which to study the genetics of cancer susceptibility. This is particularly true with regard to tumor promotion, a process that occurs in other organs and species including humans. We have studied the genetics of tumor promotion susceptibility in the mouse two-stage skin tumor model using crosses between sensitive DBA/2 or C3H and resistant C57BL/6 mice. Our results suggest that TPA promotion susceptibility is a multigenic trait. We have tentatively mapped one tumor susceptibility locus, Psl1, to mouse chromosome 9 and are currently identifying and characterizing candidate tumor susceptibility genes that map to this chromosomal region. The multistage model of carcinogenesis in mouse skin has, for more than 50 years, provided a conceptual framework from which to study the carcinogenesis process. Many concepts now currently applied to other tissues and model systems were originally derived from the mouse skin model. Because tumor promotion is an important component of carcinogenesis in humans, the identification of genes that modify response to tumor-promoting stimuli would be a significant advancement in our understanding of the genetic basis of susceptibility to cancer.

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PubMed1997

Association of a murine chromosome 9 locus (Psl1) with susceptibility to mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate.

It has been known for many years that there are dramatic differences in the susceptibility of mouse stocks and strains to two-stage skin carcinogenesis and that these differences are due the animals' responsiveness to tumor-promoting agents. In earlier studies using several inbred mouse strains, we found that susceptibility to skin tumor promotion by phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) is a multigenic trait. To extend this work, we conducted a genome scan of (C57BL/6 x DBA/2)F1 x C57BL/6 mice previously scored for sensitivity to skin tumor promotion by TPA. As a result of this scan, we now report an association of increased TPA promotion susceptibility with inheritance of the DBA/2 alleles of markers on the distal portion of mouse chromosome 9. Additional linkage analyses using (C57BL/6 x DBA/2)F2 and B x D recombinant inbred mice confirmed this association and suggested that a TPA promotion susceptibility locus maps near D9Mit51 (LODw = 4.1). We designated this locus promotion susceptibility locus 1 (Ps/1).

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PubMed1993

Localization of a novel chromosome 7 locus that suppresses development of N-Methyl-N-nitrosourea-induced murine thymic lymphomas.

N-Methyl-N-nitrosourea (MNU) is a potent carcinogen that causes the development of murine thymic lymphomas. MNU-induced tumor incidence varies considerably among different inbred mouse strains. In particular, the AKR strain is highly susceptible, whereas the C57L strain is highly resistant to MNU-induced lymphoma formation. Crosses between AKR and C57L mice were established to investigate the genetic basis for the differential susceptibility of these inbred strains. A strong association between MNU-induced lymphoma development and coat color was observed in (AKR x C57)F2 and AKR x (AKR x C57)F1 progeny such that albino mice developed a higher tumor incidence than nonalbino animals. These data suggest that a locus on chromosome 7 influences tumor development. Analysis of four additional polymorphic loci (D7Rp2, Fes, Hbb, and Int-2) on chromosome 7 in AKR x (AKR x C57)F1 backcross mice revealed a significant linkage between high tumor incidence and homozygous inheritance of AKR alleles at the albino (tyrosinase) and Hbb loci. Thus, inheritance of at least one C57L allele at the albino or Hbb loci was associated with protection against MNU-induced lymphoma development. There was no association between tumor incidence and genotype at the D7Rp2, Fes, or Int-2 loci. Taken together, the data suggest that whereas C57L mice contain a dominant tumor suppressor gene on chromosome 7, in the AKR strain both alleles at this locus are defective resulting in enhanced susceptibility to MNU-induced lymphomagenesis.

Animals↗
PubMed1991

Influence of murine leukemia proviral integrations on development of N-methyl-N-nitrosourea-induced thymic lymphomas in AKR mice.

The AKR mouse strain is characterized by a high incidence of spontaneous thymic lymphoma that appears in older animals (greater than 6 months of age) and is associated with novel provirus integrations of ecotropic and recombinant murine leukemia viruses (MuLVs). Treatment of 4- to 6-week-old AKR/J mice with the carcinogen N-methyl-N-nitrosourea (MNU) results in thymic lymphomas that arise as early as 3 to 4 months of age and contain novel somatically acquired MuLV provirus integrations. The AKR/J strain develops MNU-induced lymphoma with a higher incidence and shorter latency than has been observed for other inbred mouse strains. To determine whether provirus integrations of endogenous MuLV account for the enhanced susceptibility of the AKR strain, the incidence and latency of MNU-induced lymphoma development was compared in AKR/J and AKR.Fv-1b mice. The restrictive b allele of the Fv-1 locus restricts integration and replication of endogenous N-tropic MuLV; therefore, AKR-Fv-1b mice have a very low incidence of spontaneous lymphoma. In contrast, AKR.Fv-1b mice develop MNU-induced lymphomas with an incidence and latency similar to those of the AKR/J strain. Furthermore, thymic lymphomas from both strains express an immature CD4-8+ phenotype, indicating neoplastic transformation of the same thymocyte subset. Southern blot analysis confirmed that lymphoma DNA from AKR.Fv-1b mice did not contain somatically acquired provirus integrations. These results demonstrate that provirus integration does not contribute to the predisposition of AKR mice to develop a high incidence of early MNU-induced lymphomas. Nevertheless, MNU treatment stimulated high-level expression of infectious ecotropic MuLV in AKR.Fv-1b as well as in AKR/J mice, suggesting that viral gene products might enhance lymphoma progression.

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PubMed1989

Genetics of N-methyl-N-nitrosourea induction of thymic lymphomas in AKR/J mice: assignment of a susceptibility gene to mouse chromosome 7.

Treatment of young AKR/J mice with N-methyl-N-nitrosourea (MNU) results in the induction of a high incidence of thymic lymphomas occurring between 4 and 6 months of age. The tumor incidence is higher and the latency period is shorter than that observed in other MNU-treated mouse strains. Analysis of tumor incidence in crosses of AKR/J with C57L/J mice indicates that several genes influence the incidence and latency of MNU-induced thymic lymphomas. One of these genes appears to be tightly linked to the albino locus of chromosome 7.

Albinism↗
PubMed1989

Ecotropic virus involvement in spontaneous B-cell lymphomas of CWD/LeAgl mice.

The inbred mouse strain CWD/LeAgl, which has a high incidence of spontaneous B-cell lymphomas, expresses both ecotropic MuLV and MCF viruses. Studies indicated that the MCF viruses expressed in CWD tumors were characteristic of nononcogenic MCF viruses and that ecotropic MuLV may be the etiological agent in spontaneous B-cell lymphomagenesis. Somatically acquired proviruses of approximately the same size were detected in several tumor DNAs suggesting that integration of proviral sequences into specific regions of the mouse genome may be an important step in lymphomagenesis of this strain.

Animals↗
PubMed1988

N-methyl-N-nitrosourea-induced T-lymphomas of AKR/J mice contain somatically acquired ecotropic-like murine leukemia proviruses.

We have studied somatically murine leukemia proviral integrations in primary N-methyl-N-nitrosourea (MNU)-induced thymic lymphomas of AKR/J mice. The majority of MNU-induced lymphomas contain newly acquired murine leukemia proviral sequences. In contrast to spontaneous AKR/J lymphomas which contain multiple integrations of mink cell focus-forming recombinant proviruses, MNU-induced lymphomas contain ecotropic-related proviruses. This conclusion was based on the demonstration that EcoRI- and PvuII-digested DNA from MNU-induced lymphomas contains new 3' proviral-cellular junction fragments that hybridize with the ecotropic-specific pAKV-4 and pAKV-5 hybridization probes. Also, EcoRI/PstI double digests of DNA from MNU-induced lymphomas revealed that the acquired proviruses do not contain an internal 3' EcoRI site characteristic of mink cell focus-forming recombinant viruses. The proviral integration patterns suggest that MNU-induced lymphomas are clonal or oligoclonal in nature. This conclusion is supported by comparison of proviral integration patterns in lymphomas obtained from thymus and spleen of individual mice, and by analyses of T-cell receptor beta-chain gene rearrangements. The frequent occurrence of ecotropic-related proviral sequences in MNU-induced lymphomas suggests that these newly acquired proviruses may play a role in tumor development.

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