Mammary gland expression of mouse mammary tumor virus is regulated by a novel element in the long terminal repeat

Mouse mammary tumor virus (MMTV) infects both lymphoid tissue and lactating mammary gland during its infectious cycle, but some endogenous MMTVs are t ranscribed only in lymphoid cells. We found a lymphoid cell-specific endoge nous MMTV that was converted to a milk-borne, infectious virus through reco mbination with an exogenously transmitted MMTV. The changed expression patt ern correlated with the alteration of a single base pair in the long termin al repeat of the lymphoid cell specific virus. Transgenic mice with the ele ment from either the milk-borne or lymphoid cell-specific virus upstream of the chloramphenicol acetyltransferase reporter gene showed the same patter n of expression as the virus from which the regulatory sequences were deriv ed, Electrophoretic mobility shift assays with mammary cell extracts showed that the site from the milk-borne virus was preferentially bound by a prol actin-inducible factor that poorly bound the altered site from the lymphoid cell-specific virus. The complex that formed on the milk-borne virus-speci fic oligonucleotide supershifted with anti-Stat5b antibody. Mice lacking ei ther Stat5a or Stat5b had dramatically reduced levels of MMTV transcripts i n mammary gland but not in lymphoid tissue. Thus, a member of the STAT fami ly of transcription factors is involved in the tissue-specific expression o f mouse mammary tumor virus in vivo. This is the first example of the invol vement of a member of the STAT family of transcription factors in the contr ol of tissue-specific expression.