Timothy A. Stewart

Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes

We have produced 13 strains of transgenic mice that carry an otherwise normal mouse myc gene in which increasingly larger portions of the myc promoter region have been replaced by a hormonally inducible mouse mammary tumor virus promoter. Although expression of the fusion genes varies among these animals, the female founders of two of these transgenic strains spontaneously developed mammary adenocarcinomas during one of their early pregnancies. Both the tumors and the breast tissue of these founder animals expressed RNA transcripts corresponding to the fusion gene. Furthermore, in the best studied strain, all the available F1 female progeny that inherited the MTV/myc gene also developed mammary adenocarcinomas during their second or third pregnancies. Thus, although it has no obvious effect on the early development of these mice, the constitutionally deregulated myc gene appears to act as a heritable, predisposing factor favoring the accelerated development of a tissue-specific adenocarcinoma.

Consequences of widespread deregulation of the c-myc gene in transgenic mice: Multiple neoplasms and normal development

We have constructed a transgenic mouse strain in which a mammary tumor virus LTR/c-myc fusion gene is anomalously expressed in a wide variety of tissues. The deregulated c-myc transgene, now glucocorticoid inducible, contributes to an increased incidence of a variety of tumors, including those of testicular, breast, lymphocytic (B cell and T cell), and mast cell origin. The deregulated gene does not, however, otherwise disturb cell proliferation, nor does it interfere with normal development in these animals. Moreover, since not all tissues that express the transgene develop neoplasms, these results begin to define the transforming spectrum of the c-myc oncogene. They also extend to several organ systems the notion that elements in addition to an activated c-myc gene are required to induce malignancy in the living organism.

Parental legacy determines methylation and expression of an autosomal transgene: A molecular mechanism for parental imprinting

We have created a transgenic mouse strain in which an autosomal transgene bearing elements of the RSV LTR and a translocated c-myc gene obeys very unusual rules. If the transgene is inherited from the male parent, it is expressed in the heart and no other tissue. If it is inherited from the female parent, it is not expressed at all. This pattern of expression correlates precisely with a parentally imprinted methylation state evident in all tissues. Methylation of the transgene is acquired by its passage through the female parent and eliminated during gametogenesis in the male. These observations provide direct molecular evidence that autosomal gene expression can depend upon the sex of the parent from which the gene is inherited. They also provide a plausible mechanism for understanding parental imprinting that may be relevant to the failure of parthenogenesis in mammals, the apparent non-Mendelian behavior of some autosomal genes, and the role of methylation in gene regulation.