Faculty Bibliography

We have previously established that a dimer repeat of the complete HPV 16 genome is sufficient to cause multiple organ malignancies, either carcinomas or T-cell lymphomas, in transgenic mice. Here, we report the expression of oncogenes supporting the notion that these tumors arose via multiple oncogenic pathways. In these mice, the transgenic HPV 16 genome cosegregated with the tumor phenotype. E6/E7 expression was observed in both carcinomas and T-cell lymphomas, while E2 expression was observed only in T-cell lymphomas. Some of the T-cell lymphomas revealed E2 expression alone, implying that oncogenic pathways of HPV other than the one involving E6/E7 existed in these transgenic mice. To establish that this is the case, expression of genes downstream from E6/E7 and oncogenes involved in T-cell lymphoma formation were analyzed. p53 mutations were observed in two of five tumors that lacked E6 expression. High levels of c-myc gene expression were observed in five of six tumors with E7 expression, suggesting that a pathway involving E7, inactivation of Rb, and activation of c-myc is important in tumorigenesis of HPV 16 in these transgenic animals. High levels of expression of the c-Pim gene were also noted in two of three c-myc-expressing T-cell lymphomas, suggesting cooperation between these two proto-oncogenes. Activation of Hox-11, Tal2/SCL-2, and Rbtn1/Ttg1 expression, which are highly associated with human T-cell acute lymphoblastic leukemia (T-ALL), was observed in three of three T-cell lymphomas with E2 expression but not E6/E7 expression, showing that pathways to tumor formation not involving E6/E7 exist in these transgenic animals. At least two oncogenic pathways to tumors in HPV 16 transgenic mice exist, one involving E6/E7 and c-myc and the other involving E2 and lymphomagenic oncogenes.

BACKGROUND: GLI is an oncodevelopmental gene in the vertebrate hedgehog/patched signaling pathway that is spatiotemporally regulated during development and is amplified in a subset of human cancers. GLI is the prototype for the Gli-Kruppel family of transcription factors, which includes the Drosophila segment polarity gene ci, the C. elegans sex-determining gene tra-1, and human and mouse GLI3, all of which contain a conserved domain of five C2-H2 zinc fingers. GLI3 mutations have been implicated in the mouse mutant extra toes, as well as in human Greig cephalopolydactaly syndrome and the autosomal dominant form of Pallister-Hall syndrome. As such, GLI and the vertebrate hedgehog/patched signaling pathway appear to play important roles in both normal development and neoplasia. MATERIALS AND METHODS: Since it is not known whether aberrant GLI expression is similarly linked to developmental disorders, we developed gain-of-function transgenic mice which express human GLI ectopically. RESULTS: Affected transgenic mice exhibit a phenotype of failure to thrive, early death, and Hirschsprung-like patches of gastrointestinal dilatation. The colons of affected mice have greatly attenuated smooth muscle layers and abnormal overlying epithelium. The density of myenteric plexuses is reduced in the colonic walls. The severity of the phenotype is related to the level of transgene expression. CONCLUSIONS: The transgenic mouse model supports a role for GLI in gastrointestinal development. As part of the vertebrate hedgehog/patched signaling pathway, GLI is essential to mesoderm and CNS ectoderm development and transgenic GLI expression affects neuronal, muscular, and epithelial cell differentiation in the gut. Expression of human GLI in mice results in impairment of enteric neuronal development and a Hirschsprung-like phenotype.

Human papillomavirus type 16 is highly associated with cervical carcinoma. Here we report families of transgenic mice produced by the microinjection of a dimer repeat sequence of the human papillomavirus type 16 genome. Thirty-two transgenic animals in four families developed multiple organ malignancies that appeared in middle age without other intervention. The tumor phenotype of poorly differentiated carcinomas or malignant lymphomas and the transgene cosegregate in these lineages. The tumors arise in the subcutaneous compartment, thoracic cavity, or abdomen; are widely metastatic; and grow rapidly in nude mice. No cervical lesions were identified in six females examined. No rearrangements in transgene E6/E7, E2, and E1 regions were found in tumor tissues, and the truncated E2 region, which was thought to play an important role in human cervical carcinogenesis, was not needed for tumorigenesis in these animals. The transgenic mice produce RNA from the E6/E7 open reading frames, which has been identified in both the carcinomas and the lymphomas, but RNA from the E2 open reading frame is present only in malignant T-cell lymphomas and not in carcinomas, hyperplastic lymphoid tissue, or normal lymphoid tissue.