Possible role of the first intron of c-H-ras in gene expression: anti-cancer elements in oncogenes.

When members of ras gene family, which encode structurally related proteins of approximately 21,000 daltons (p21), are activated by either structural mutations or enhanced promoter activities, immortalized mammalian cells can be transformed into malignant forms. The ras genes are classified as "housekeeping genes" which express relatively constantly at low levels in all tissues and throughout all developmental stages. It is therefore important to understand how regulatory, cis-acting in particular, elements of the genes control their expression. We have previously reported that the principal promoter, 51 bp long or less, located around 1370 bp upstream from the first coding ATG, plays the most important role for expression, though there seem to be residual promoter activities further downstream as well. The most upstream mRNA start site is located at the 3'-end of the principal promoter, which lies directly adjacent to the homologous sequence between human and rat c-H-ras 5'-flanking regions. It is therefore proposed that the c-H-ras gene may have a dispersed promoter in which the principal promoter and subpromoters may be distributed. On the other hand, the first intron region seems to contain two sets of positive and negative elements which appear to have, respectively, a positive and negative influence on the efficiency of focus formation with the activated c-H-ras oncogene. From testing done in our laboratory, it was further revealed that these cis-acting elements in the intron affect c-H-ras gene expression at the post-transcriptional level. The middle part of the first intron was in fact shown unusually conserved between human and rat DNA sequences. Moreover, computer analyses revealed that the intron sequences of various oncogenes (both human and rodent sequences available from GenBank DNA sequence data-bank) such as ras, fos, c-myc, N-myc and int-1, are in general significantly more highly conserved when compared with sequences of non-oncogene introns. The significance of this oncogene-related conserved sequence is discussed and the proposal is made that it may function as an "anti-cancer element" or "safety valve" against gene truncation/translocational activation of oncogenes.