Negative regulation in correct tissue-specific expression of mouse mammary tumor virus in transgenic mice.

Abstract

Tissue-specific expression of genes is achieved, at least in part, by the presence of specific sequences termed enhancer elements, usually located upstream of transcription initiation sites (39). Some of these elements represent binding sites for ubiquitous trans-acting factors which increase the expression of genes containing these binding sites in a number of different cell types, whereas other elements are apparently recognized by factors found only in specific cell types. It is these latter factors that contribute, at least in part, to the tissue-specific expression of genes.Negative regulation also has been reported to influence gene expression in specific cell types (24,45). Some, if not all, genes contain both positive enhancer elements and negative regulatory elements (NREs), which may act as binding sites for factors which inhibit gene expression, possibly by interfering with the binding of positively acting factors (1,2,38). In addition, a number of retroviral long terminal repeats (LTRs) have been shown to encode NREs which suppress transcription (5, 14, 37).The endogenous murine retrovirus mouse mammary tumor virus (MMTV) is expressed in several tissues (18). When transgenic mice were made by using reporter genes under the transcriptional control of the MMTV LTR, the transgenes were expressed in the same tissues as was the endogenous virus, namely, the epithelial cells of the mammary and salivary glands, lungs, kidneys, and seminal vesicles and the lymphoid cells of the spleen and thymus (9,26,41,42

CDP Is a Repressor of Mouse Mammary Tumor Virus Expression in the Mammary Gland

“…Previous experiments have shown that high levels of MMTV transcription in the lactating mammary gland result from the action of positive factors, including those that bind to the HRE and the mammary gland-specific enhancer in the LTR (28,37,46,47,55,69). However, little is known about negative regulation of MMTV expression in the mammary gland.…”

“…We have shown that the levels of full-length CDP decline during mammary gland differentiation, a period when MMTV transcription increases (25,55). DNase I mapping experiments using the MMTV pNRE revealed the presence of two CDP binding sites.…”

“…The disease specificity of MMTV appears to be linked directly to high viral expression in specific tissues (68). Milk-borne MMTV is expressed primarily in the lactating mammary gland (55). The high level of viral transcription increases MMTV insertions, leading to cell transformation in mammary tissue.…”

“…Removal of NREs relieved the suppression of MMTV transcription in normally semipermissive or nonpermissive tissues. Transgenic mouse experiments with p1BCAT, a naturally occurring LTR deletion (Ϫ655 to Ϫ165) mutant linked to the gene for chloramphenicol acetyltransferase, revealed that this LTR deletion mutation allows high-level viral expression in semipermissive tissues (e.g., thymus) and lower expression in tissues that are normally nonpermissive (brain, heart, and skeletal muscle) (55). Transienttransfection assays with sequential LTR deletion mutants have defined two NREs, promoter distal and promoter proximal (see Fig.…”

What retroviruses teach us about the involvement of c-Myc in leukemias and lymphomas

“…In agreement with this conclusion, mice carrying an MMTV LTR-Myc transgene induce mammary carcinomas as well as some lymphomas, 100 and the MMTV LTR has been shown to be expressed in mammary cells and B and T lymphoid cells. 101,102 Such experiments highlight the fact that overexpression of c-Myc does not lead exclusively to induction of leukemias and lymphomas, but that overexpression is dependent on the nature of the enhancer associated with c-Myc.…”