We will investigate the role of the protein producs of the long terminal repeat (LTR) region of mouse mammary tumor virus (MMTV) in the life cycle of MMTV, and in tumorigenesis by MMTV. The transformation-specific characteristics of spontaneous T cells leukemias of DBA/2 mice (ML cells) will be studied, and the possible leukemogenic activity of MMTV investigated. We will raise antisera against synthetic peptides predicted by the LTR open reading frame, and an expression vector containing MMTV LTR sequences will be used to obtain purified LTR protein for polyclonal antiserum, and monoclonal antibody production. These reagents will be used to analyze normal and neoplastic mouse tissues for the expression and distribution of pLTRs. The effect of various hormones on the expression of pLTR will be tested in primary cultures of mouse tissues growing on floating collagen gels. The role of MMTV in ML cells will be investigated by analyzing MMTV LTR specific mRNAs that are transcribed in high levels in these cells. We will test whether acquired deleted proviruses with truncated LTRs are a consistent feature of ML cells. Acquired deleted proviruses will be cloned in order to define the deletions in the LTR. The leukemogenic potential of MMTV will be tested by intrathymic injection of young DBA/2 mice with the milk virus. ML cells will also be examined for the presence of MCF like proviruses, and enhanced expression of known oncogenes. The 15,000 Mr transformation-specific protein of ML cells, that is detected by using the NIH-3T3 transfection assay, will be characterized, and DNA sequences encoding it will be cloned. The cloned gene will be used to probe for enhanced expression in tumor tissues, association with proviruses and homology to any of the known oncogenes. Since the LTR region of MMTV probably plays an essential role in the transforming activity of MMTV, it is essential for the understanding of tumorigenesis by MMTV, that the role of the LTR gene product be understood. The study of ML cells might contribute to an understanding of the mechanism of transformation by slowly transforming retroviruses, and should add to our understanding of oncogenesis.
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