We describe methods and DNA constructs/engineered mammalian promoters to enhance native promoter activity while retaining inherent regulation by inserting multi-copy response elements (REs) into non-adjacent locations. Multiple copies of REs are clustered in a group forming a transcription factor response element segment. The segment is at least duplicated in tandem upstream of the ATG start codon. Spacers of 0.2-0.7 kilo base pairs are introduced between the two segments and smaller spacers of about between 9-15 bp are introduced between the copies of REs within a segment.