Patients with the acquired immunodeficiency syndrome are at risk to develop a variety of different cancers. Based on epidemiolÃ3gica! data, Kaposi's sarcoma and non-Hodgkin's lymphoma have been clearly asso ciated with infection by the human immunodeficiency virus (HIV). Ad ditional cancers such as basal cell and squamous cell carcinomas, mela noma, and hepatocellular carcinoma have also been reported to be asso ciated with a diagnosis of acquired immunodeficiency syndrome. A direct causal role of HIV has yet to be established for any of these cancers. We now report that transgenic mice carrying the HIV tat gene develop a high incidence of hepatocellular carcinoma after a long latency and that these changes in the liver are likely to be initiated by extrahepatic growth signals from the tat expressing cells in these mice. We predict that as acquired immunodeficiency syndrome patients begin to respond to ther apy and show prolonged survival, such "secondary" malignancies induced by HIV will become increasingly prevalent.

Three cell groups, neural stem/progenitor cells (NS/PCs) dissociated from the embryonic day 11 (E11) rodent cerebral cortex, expanded NS/PC cultures, and cultured neurons from E15, were used to conduct a genomic study with differential display (DD). The mouse Af1q, homologue of human AF1q, was found to be significantly up-regulated during the neuronal production from NS/PCs. The ectopic expression of human AF1q triggered the expression of the neuronal marker TuJ1 in non-neuronal human embryonic kidney (HEK) cells.

There is unequivocal evidence that a relatively nonpolymorphic class I gene (designated Q10) from the Qa region of inbred mice encodes a secreted class 1 molecule. We have used a cDNA probe specific for this gene and an antiserum specific for its secreted protein product to investigate the occurrence and expression of this gene in different species of wild mice broadly representing the entire genus Mus. Evidence is presented that a Q10-like gene has been conserved and is transcribed and translated throughout the genus, suggesting that it serves an important function. However, the data also show that some differences have appeared in this gene over the period of evolutionary time covered by this sampling of wild mice. These results indicate that a specific class I DNA probe isolated from inbred mice can be used to discriminate a particular gene among the multiple class I genes present in other species.

liver, intestine and testis, but only minute amounts in the thymus, spleen and kidney. Zinc administration resulted in a 1.5- and 8.5-fold increase in H-2D d expression in the liver and the intestine, respectively, but did not affect expression in the other organs tested. T cell toler- ance developed towards H-2D d in MTD mice, even in the absence of zinc. In contrast, NK cell-mediated natural resistance against lymphoma grafts was not seen in MTD mice, despite zinc administration. NK cells in MTD mice also failed to develop self tolerance to H-2D d . The lack of functional effects did not result from inability of NK cells in MTD mice to interact with H-2D d , as down-regulation of Ly49A receptor expression was observed on liver NK cells in MTD mice. Our data reveal a difference between T cells and NK cells in their requirements for MHC class I molecules in specificity development.

We have studied natural killer (NK) cell tolerance in a major histocompatibility complex (MHC) class I transgenic line, DL6, in which the transgene product was expressed on only a fraction of blood cells. In contrast with transgenic mice expressing the same transgene in all cells, NK cells from mosaic mice failed to reject transgene-negative bone marrow or lymphoma grafts. However, they retained the capability to reject cells with a total missing-self phenotype, i.e., cells lacking also wild-type MHC class I molecules. Tolerance against transgene-negative cells was demonstrated also in vitro, and could be broken if transgene-positive spleen cells of mosaic mice were separated from negative cells before, or after 4 d of culture in interleukin-2. The results provide support for selective NK cell tolerance to one particular missing-self phenotype but not to another. We suggest that this tolerance is determined by NK cell interactions with multiple cells in the environment, and that it is dominantly controlled by the presence of cells lacking a specific MHC class I ligand. Furthermore, the tolerant NK cells could be reactivated in vitro, which suggests that the tolerance occurs without deletion of the potentially autoreactive NK cell subset(s), and that it may be dependent upon the continuous presence of tolerizing cells.

In familial neurofibromatosis type 1 (NF1), individuals with a germ line-transmitted NF1 mutation develop multiple neurofibromas. To explain the observation that transgenic mice expressing the human T-lymphotropic virus type 1 (HTLV-1) tax gene under the control of the viral regulatory element also develop multiple neurofibromas, we demonstrate that the Tax trans-regulator can functionally repress NF1 gene expression through a cis-acting element located immediately upstream of its transcriptional start site, thereby allowing the development of benign neurofibromas without the need for direct mutations in NF1. We propose that such a mechanism would suffice to epigenetically alter NF1 gene expression. The fact that transgenic animals have localized rather than diffuse neurofibroma formation, however, suggests that additional genetic or epigenetic events may be required for neurofibroma formation.

A new member of the mouse NK family of homeobox genes that is related to Drosophila NK-3 has been identified. Expression of this gene, termed Nkx-3.1, is largely restricted to the prostate gland in adult animals. The level of Nkx-3.1 mRNA decreases markedly in response to castration, suggesting that its expression is androgen-dependent. In situ hybridization analyses demonstrated that expression of Nkx-3.1 in the prostate is confined to epithelial cells. In newborns, Nkx-3.1 mRNA is detected in the urethral epithelium that is being induced by the surrounding mesenchyme to invaginate to form prostatic buds. Together, these observations suggest that the Nkx-3.1 protein, which likely functions as a transcription factor, plays a prominent role both in the initiation of prostate development and in the maintenance of the differentiated state of prostatic epithelial cells.

TGFb 1 has been implicated in the pathogenesis of liver disease. The high frequency of detection of the hepatitis B virus X (HBx) antigen in liver cells from patients with chronic hepatitis, cirrhosis, and liver cancer suggested that expression of HBx and TGFb 1 may be associated. To test this possibility, we examined the expression of TGFb 1 in the liver of transgenic mice expressing the HBx gene. We show that the patterns of expression of TGFb 1 and Hbx protein are similar in these mice and that HBx activates transcription of the TGFb 1 gene in transfected hepatoma cells. The cisacting element within the TGFb 1 gene that is responsive to regulation by Hbx is the binding site for the Egr family of transcription factors. We further show that the Egr-1 protein associates with the HBx protein, allowing HBx to participate in the transcriptional regulation of immediate–early genes. Our results suggest that expression of Hbx might induce expression of TGFb 1 in the early stages of infection and raise the possibility that TGFb 1 may play a role in hepatitis B virus pathogenesis. ( J. Clin. Invest. 1996. 97:388 – 395 . )

Radiation Oncology InvestigationsVolume 3, Issue 6 p. 257-261 Oncogenes/Tumor Suppressor Gene Epigenetic modulation of tumor suppressor genes in the development of cancer Lionel Feigenbaum Ph.D., Department of Virology, Jerome H. Holland Laboratory, Rockville, MarylandSearch for more papers by this authorHiroyuki Ueda M.D., Department of Virology, Jerome H. Holland Laboratory, Rockville, MarylandSearch for more papers by this authorGilbert Jay Ph.D., D.Sc., Corresponding Author Department of Virology, Jerome H. Holland Laboratory, Rockville, MarylandDepartment of Virology, Jerome H. Holland Laboratory, Rockville, MD 20855Search for more papers by this author Lionel Feigenbaum Ph.D., Department of Virology, Jerome H. Holland Laboratory, Rockville, MarylandSearch for more papers by this authorHiroyuki Ueda M.D., Department of Virology, Jerome H. Holland Laboratory, Rockville, MarylandSearch for more papers by this authorGilbert Jay Ph.D., D.Sc., Corresponding Author Department of Virology, Jerome H. Holland Laboratory, Rockville, MarylandDepartment of Virology, Jerome H. Holland Laboratory, Rockville, MD 20855Search for more papers by this author First published: 1995 https://doi.org/10.1002/roi.2970030602AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Volume3, Issue6Special Issue: Workshop on Neoplastic Transformation in Human Cell Systems in Culture: Mechanisms of Cercinogenesis September 7–9, 1995, Chicago, Illinois1995Pages 257-261 RelatedInformation

To test whether the hypothesis that the Alzheimer's A beta peptide is neurotoxic, we introduced a transgene into mice to direct expression of this peptide to neurons. We show that the transgene is expressed in brain regions which are severely affected in Alzheimer's disease resulting in extensive neuronal degeneration. Morphological and biochemical evidence indicates that the eventual death of these cells occurs by apoptosis. Coincident with the cell degeneration and cell death is the presence of a striking reactive gliosis. Over 50% of the transgenic mice die by 12 months of age, half the normal life span of control mice. These data show that A beta is neurotoxic in vivo and suggest that apoptosis may be responsible for the accompanying neuronal loss, the principal underlying cellular feature of Alzheimer's disease.

Recent investigations have shown the presence of ras gene mutations and human papillomavirus (HPV) DNA in prostate carcinomas. In the present study, secondary adult human prostatic epithelial cells, upon transfection with a plasmid containing the entire HPV-18 genome, acquired an indefinite life-span in culture but did not undergo malignant conversion. Subsequent infection of these immortalized cells with the Kirsten murine sarcoma virus, which contains an activated Ki-ras oncogene, induced morphological transformation that led to the acquisition of neoplastic properties. These findings demonstrate the malignant transformation of adult human prostate epithelial cells in culture by a combination of viral oncogenes and the successive roles of HPV infection and Ki-ras activation in a multistep process responsible for prostate carcinogenesis.

During the last decade, an understanding of the causes of many human diseases has progressed rapidly, in large measure because of the development of technologies that allow us to identify the genes that are involved. Identification of a gene that is suspected to play an important role in a particular disease opens up a whole new dimension of research to understand the molecular events that underlie the cause of that disorder. A crucial step in this process is often the development of an animal model of the disease. Again, the last decade has seen rapid advances in our ability to create such models, particularly in mice. Technologies that allow for the addition, alteration, of elimination of individual genes from the genome to create a transgenic mouse are now routine. The advantages of having a transgenic mouse model of a human disease are many. These animals often provide the first unequivocal proof that a particular gene is responsible for causing the pathological changes that occur with disease. They also can provide a system to carefully dissect the successive events that lead to the disease state, and can provide a custom-designed whole animal system to test potential therapies to treat and eventually cure the disease. Most important, new concepts relating to gene expression and gene function in disease often emerge from such transgenic studies. This review will illustrate several examples in which transgenic animals have contributed significantly to the evolution of concepts of the underlying mechanisms of human disease.

The human T-lymphotropic virus type I (HTLV-I) Tax protein is a transcriptional regulatory protein that has been suggested to play a causal role in the development of several HTLV-I-associated diseases. Tax regulates expression of its own LTR and of certain cellular promoters perhaps by usurping the function of the host transcriptional machinery. We have established a transgenic mouse model system to define the spectrum of tissues in vivo that are capable of supporting Tax-mediated transcriptional transactivation. Transgenic mice carrying the HTLV-I LTR driving expression of the Escherichia coli β-galactosidase (βgal) gene were generated, and this LTR-βgal gene was transcriptionally inactive in all tissues. When LTR-βgal mice were mated to transgenic mice carrying the same LTR driving expression of the HTLV-I tax gene, mice that carried both transgenes showed restricted expression of the βgal reporter gene in several tissues including muscle, bone, salivary glands, skin, and nerve. In addition, a dramatic increase in the number of βgal-expressing cells was seen in response to wounding. These observations provide direct evidence for viral transactivation in vivo, delimit the tissues capable of supporting that transactivation, and provide a model system to study the mechanism of gene regulation by Tax.