MMTV is a type B retrovirus that induces mammary carcinomas or T- cell lymphomas in mice. The specificity of MMTV-induced diseases is related directly to its tissue-specific expression. Deletion of the 3' portion of the U3 region in the MMTV long terminal repeat (LTR) is sufficient to increase MMTV expression in certain cell types, including T cells, in both transgenic mice and in transient transfection assays. In addition, deletion of specific U3 sequences changes a mammary tumor-inducing MMTV into a strain that induces T- cell lymphomas. The U3 deletions found in lymphoma-inducing MMTVs invariably lose at least two negative regulatory elements (NREs) that appear to control the tissue-specific expression of MMTV through interaction with trans-acting factors encoded by the host cell. One of these trans-acting factors known as Cux or CCAAT displacement factor (CDP) is a homeodomain protein involved in the repression of genes expressed in the terminal stages of differentiation. The goal-of this proposal is to investigate the role of Cux in the control of tissue-specific MMTV transcription. This will be accomplished as follows. (l) The effect of Cux overexpression on MMTV transcription will be investigated in HC11 cells that can be induced to differentiate in the presence of lactogenic hormones. (2) Cux will be depleted in HC11 cells using anti-sense expression vectors, and the effects on MMTV transcription will be determined. (3) Transgenic mice that overexpress Cux in specific tissues will be monitored for MMTV expression and tumor formation. These experiments should provide a model system for determining the role of negative regulation in tissue-specific transcription. Such studies will improve our general understanding of gene expression and its role in oncogenesis.
