THE CIS-ACTING ELEMENTS KNOWN TO REGULATE C-MYC EXPRESSION EX-VIVO ARE NOT SUFFICIENT FOR CORRECT TRANSCRIPTION IN-VIVO

Much of our knowledge about the regulation of the c-myc proto-oncogene expression has come from studies of c-myc gene expression in several well defined ex vivo systems, including differentiation systems and tu mor cells. However, very few investigations have been performed to det ermine the factors and cis-acting sequences that regulate c-myc expres sion in vivo. In order to obtain information on the sequences required to regulate c-myc gene transcription from the two major P1 and P2 ini tiation sites in the mouse, we have generated several constructs conta ining human or murine c-myc genomic sequences with various 5' flanking sequences and derived corresponding transgenic mice. A sensitive S1 n uclease protection assay was performed to analyse and to compare trans gene expression with that of the endogeneous c-myc mRNA, either in adu lt organs, or during development. None of the transgenic mice expresse d the construct appropriately, although several strains exhibited unex pected expression most probably due to position effects. Our results i ndicate that the cis-acting elements described to regulate c-myc expre ssion ex vivo are not sufficient to drive the correct expression of c- myc gene in vivo and strongly suggest that additional regulatory eleme nts located upstream from -3500 (with respect to mouse P1 promoter) an d downstream 1500 bp from polyadenylation sites are required.