MOUSE MAMMARY-TUMOR VIRUS SEQUENCES RESPONSIBLE FOR ACTIVATING CELLULAR ONCOGENES

Integration of mouse mammary tumor virus (MMTV) near the int genes res ults in the inappropriate expression of these proto-oncogenes and init iates events that lead to the formation of mammary adenocarcinomas. In most cases, the MMTV provirus integrates in a transcriptional orienta tion opposite that of the int genes. We have used a novel, vector-base d system designed to recapitulate the integration of MMTV upstream of the int-2 promoter. Compared to a cellular promoter or another retrovi ral promoter, the MMTV long terminal repeat (LTR) in this configuratio n is particularly efficacious at activating the int-2 promoter. The se quences responsible for enhancing the activity of the int-a promoter m ap to two domains in the 5' end of the MMTV LTR. One domain is a previ ously defined element; the second is an element delineated by these st udies that acts synergistically with the first. Both of these elements display mammary cell-specific activity. Thus, even though the MMTV pr omoter itself is weak without hormonal stimulation, viral integration can position the 5' LTR elements to efficiently activate transcription from cellular proto-oncogenes. Other functional elements in the LTR h ave little effect on the activation of the int-2 promoter. Even stimul ation of the MMTV promoter with steroid hormones only modestly activat es transcription from the int-2 promoter, suggesting that the 5' eleme nts of the LTR are the predominant determinants of the tissue- and ori entation-specific activation of cellular promoters by MMTV.