▪ Abstract Interleukin-4 is a multifunctional cytokine that plays a critical role in the regulation of immune responses. Its effects depend upon binding to and signaling through a receptor complex consisting of the IL-4Rα chain and the common gamma chain (γc), resulting in a series of phosphorylation events mediated by receptor-associated kinases. In turn, these cause the recruitment of mediators of cell growth, of resistance to apoptosis, and of gene activation and differentiation. Here we describe our current understanding of the organization of the IL-4 receptor, of the signaling pathways that are induced as a result of receptor occupancy, and of the various mechanisms through which receptor function is modulated. We particularly emphasize the modular nature of the receptor and the specialization of different receptor regions for distinct functions, most notably the independent regulation of cell growth and gene activation.

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The IL-4 receptor: signaling mechanisms and biologic functions.

Evidence from sero-epidemiological studies and from cell culture studies supports the hypothesis that the cells of many, and perhaps all, vertebrates contain information for producing C-type RNA viruses. It is postulated that the viral information (the virogene), including that portion responsible for transforming a normal cell into a tumor cell (the oncogene), is most commonly transmitted from animal to progeny animal and from cell to progeny cell in a covert form. Carcinogens, irradiation, and the normal aging process all favor the partial or complete activation of these genes. An understanding of how normal cells and normal animals prevent expression of endogenous viral information would appear to offer one of the best hopes for the control of naturally occurring cancers.

https://www.pnas.org/content/pnas/64/3/1087.full.pdf

Oncogenes of rna tumor viruses as determinants of cancer

The endogenous ecotropic murine leukemia virus DNA content and integration sites were characterized for 54 inbred strains and substrains of mice by restriction enzyme digestion, Southern blotting, and hybridization with an ecotropic murine leukemia virus DNA-specific probe. More than 75% of these strains carried endogenous ecotropic proviruses which were located in at least 29 distinct integration sites in chromosomes of Mus musculus. Fourteen of these proviruses have been assigned specific locus designations. Most, but not all, of the endogenous ecotropic proviruses were structurally indistinguishable by this analysis from the prototype AKR ecotropic virus, and the distribution of these proviruses followed known relationships among the inbred strains and substrains of mice. These results suggest that, in general, viral DNA integration preceded the establishment of inbred mouse strains and that these integrations are relatively stable.

Organization, distribution, and stability of endogenous ecotropic murine leukemia virus DNA sequences in chromosomes of Mus musculus.

Neuroblastoma is a type of cancer that most often affects children. Neuroblastoma occurs when immature nerve cells called neuroblasts become abnormal and multiply uncontrollably to form a tumor. Most commonly, the tumor originates in the nerve tissue of the adrenal gland located above each kidney. Other common sites for tumors to form include the nerve tissue in the abdomen, chest, neck, or pelvis. Neuroblastoma can spread (metastasize) to other parts of the body such as the bones, liver, or skin.

Neuroblastoma

Publisher Summary The question that whether the unit of malignancy is a gene, or an organism that grows in highly specialized protoplasmic environments, or a molecule that multiplies by virtue of integral chemical union with a molecule of protoplasm, remains unanswered. The question of whether leukemia in the mouse is caused by either genetic or viral mechanisms has taken on a new meaning with the recognition of host genetic constitution with the viral infection in leukemogenesis. The chapter covers the early studies of murine leukemia and the genetic control of friend virus susceptibility and naturally occurring leukemia viruses. It also discusses the h2 linked genetic control of leukemogenesis and the other genes responsible for leukemogenesis. Infection with ontogenic viruses is complex and malignancy is not an inevitable result of tumor virus infection; many specific events affect the interaction of leukemia virus with cells, leading to leukemogenesis.

Genetic Control Of Murine Viral Leukemogenesis

Tests for the group-specific antigen of the C-type RNA tumor virus showed that mouse embryos of all strains tested, at some stage of development in utero, revealed detectable titers of group-specific antigen in one or more of their tissues; younger, rather than older, embryos were likely to be positive, particularly in those strains which normally reveal little or no expression of the RNA genome postnatally. The antigens were found in embryos of low-leukemia strains, free of infectious virus. These new findings support a previously stated hypothesis that the genome of RNA tumor viruses, mostly switched off for infectious virus expression, is vertically transmitted as part of the natural genetic apparatus of normal mouse cells. Since group-specific antigens have also been described in chick embryos and immunological tolerance to homologous group-specific antigens has been demonstrated in hamsters and cats as well as in mice and chickens, the hypothesis has been extended to include vertebrate cells in general. Finally, the high incidence and titers of the group-specific antigen suggest that the genes for RNA tumor virus, which later in life act as determinants of cancer, may be important also as gene determinants in the developing embryo.

Group-Specific Antigen Expression During Embryogenesis of the Genome of the C-Type RNA Tumor Virus: Implications for Ontogenesis and Oncogenesis

Leukemia was observed in 45 per cent of hairless mice at 8 to 10 months of age and 72 per cent at 18 months. The incidence of leukemia in normal heterozygous mice of the same age is about one per cent at 10 months and increases to 20 per cent at 18 months. Other tumors are rare; two mammary adenocarcinomas occurred in heterozygotes, and an epidermal squamous cell carcinoma was found in a hairless mouse. Murine leukemia virus was isolated from normal and leukemic mice of both genotypes on SWR/J- and C57L/J-METC, but not BALB/cJ-METC. If this virus is responsible for the leukemia in HRS/J mice, the mutant gene (hr) enhances susceptibility and the wild-type allele (+) induces resistance to leukemogenesis, i.e., malignant transformation of reticulo-endothelial tissues occurs rather than inhibition of viral replication as both genotypes harbor virus in high titers. The two types of HRS/J mice, hr/hr and hr/+, are congenic, i.e., they differ only with respect to one allele (hr or +) at the mutant locus. This single gene difference should lend itself to analysis of the interaction of a specific gene and murine leukemia virus.

GENETIC CONTROL BY THE hr-LOCUS OF SUSCEPTIBILITY AND RESISTANCE TO LEUKEMIA

Prevalence of murine C-type RNA virus group specific antigen in inbred strains of mice

AFTER the description of the cell-free transmission of neuroblastoma C1300, a transplantable tumour in strain A/J mice, by Prasad et al.1, we made ten attempts to reproduce their results, first using their extraction procedure and then by using the viral concentration procedure of Moloney2, modified by Huebner et al.3. We inoculated twenty-eight prenatal, forty-seven newborn, and sixteen 4-week-old A/J mice but failed to obtain positive results, even after 100 days postinoculation. Because we used newborn mice that are usually more susceptible to oncogenic viruses than the older mice used by Prasad et al., and viral concentrates rather than filtrates, we expected to increase our chances of transmission.

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D. D. Myers

Papers

Group-Specific Antigen Expression During Embryogenesis of the Genome of the C-Type RNA Tumor Virus: Implications for Ontogenesis and Oncogenesis

GENETIC CONTROL BY THE hr-LOCUS OF SUSCEPTIBILITY AND RESISTANCE TO LEUKEMIA

Prevalence of murine C-type RNA virus group specific antigen in inbred strains of mice

Cell-free transmission of mouse neuroblastoma.

Differential effect of a synthetic polyribonucleotide complex on spontaneous and transplanted leukemia in mice.