REGULATORY ELEMENT IN THE MMTV LTR

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DESCRIPTION: Mouse mammary tumor virus (MMTV) causes breast cancer in mice by integrating a copy of its genome into the host chromosome, thereby altering the expression of cellular genes which now come under control of viral signals. The expression of the virus, and adjacent host genes, is tissue-specific and sensitive to steroid hormones. The response to steroid hormones is mediated by binding of the hormone receptor to a recognition sequence within the long terminal repeat (LTR) region of the proviral genome. An 18 bp sequence adjacent to the hormone receptor binding site has been identified as additionally required for the hormone response and is capable of binding host cellular proteins in a tissue-specific fashion. The 18 bp sequence is variable among MMTV strains and is missing from a strain isolated from a kidney carcinoma. The hypothesis for the proposed studies is that the 18 bp sequence partially determines the specificity of MMTV for replication and tumorigenesis in the mammary gland. The sequence mediates this effect by binding transcriptional regulatory factors. The specific aims are: 1) to test the activity in mammary and kidney cells of a reporter gene linked to the MMTV LTR with deletions or alterations of this region; 2) to test the tissue tropism and relative tumorigenicity of recombinant viruses differing only in the 18bp region; 3) to obtain and determine the nucleotide sequence of molecular clones of cDNAs encoding proteins capable of specifically binding the 18 bp sequence; 4) to test the tissue distribution of transcript encoding the 18 bp binding protein. It is expected that the mouse proteins thus identified will play a role in mediating the normal host response to steroid hormones, and that human homologs may be identified that function similarly. The elucidation of the 18 bp element's role in the steroid response and the identification of factors that carry out the effect may suggest strategies to block such responses therapeutically.