Wright S, Mirels L F, Calayag M C, Bishop J M
Department of Microbiology and Immunology, University of California, San Francisco 94143.
Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11383-7. doi: 10.1073/pnas.88.24.11383.
Modulation of transcriptional elongation within the c-myc gene is thought to play a major role in determining levels of c-myc mRNA in both normal and tumor cells. A discrete site of blockage to transcriptional elongation has previously been localized at the 3' end of exon 1 of the mouse and human c-myc genes. We here identify an additional site of transcriptional attenuation that is located between the P1 and P2 promoters of the c-myc gene and that mediates premature termination of transcripts initiating from the P1 promoter. A 95-nucleotide DNA fragment derived from this region prematurely terminated transcription when placed downstream from the promoter of the H-2Kbm1 gene and assayed by expression in Xenopus oocytes. We also show that the previously identified attenuation signal in exon 1 of the mouse c-myc gene can mediate premature termination of P1-initiated transcripts. Premature termination of P1-initiated transcripts presumably increases transcription from the downstream P2 promoter; aberrant regulation of this termination may explain the increased use of the P1 promoter that is characteristic of certain tumors in which myc is overexpressed.
c-myc基因内转录延伸的调控被认为在决定正常细胞和肿瘤细胞中c-myc mRNA水平方面起着主要作用。先前已将转录延伸的一个离散阻断位点定位在小鼠和人类c-myc基因外显子1的3'端。我们在此鉴定出另一个转录衰减位点，它位于c-myc基因的P1和P2启动子之间，并介导从P1启动子起始的转录本的过早终止。当从该区域衍生的一个95个核苷酸的DNA片段置于H-2Kbm1基因启动子下游并通过非洲爪蟾卵母细胞中的表达进行检测时，它能过早终止转录。我们还表明，先前在小鼠c-myc基因外显子1中鉴定出的衰减信号可以介导P1起始转录本的过早终止。P1起始转录本的过早终止可能会增加下游P2启动子的转录；这种终止的异常调控可能解释了某些myc过表达肿瘤中特征性的P1启动子使用增加的现象。
