Transcriptional regulation of the dihydrofolate reductase/rep-3 locus

This review summarizes many studies that have used the mouse, hamster, or human dihydrofolate reductase locus as a model system for the study of basal or regulated transcription. This locus encodes two genes, dhfr and rep-3, that are oriented in opposite directions. The dhfr promoter and the two rep-3 promoters are highly GC-rich and do not contain consensus TATA boxes. The cis-acting elements important in basal transcription of these non-TATA box promoters have been mapped, revealing that Sp1 plays a dominant role, and that sequence elements both upstream and downstream of the initiation site contribute to transcriptional activity. Future studies will be directed toward understanding the assembly of transcription complexes on these promoters. The expression of the dhfr gene following treatment of cells with many different stimuli has been analyzed, and in many, but not all, cases the response has been at the transcriptional level. In those systems where the regulatory cis-acting element has been mapped, the E2F sites flanking the transcription initiation site play a central role in mediating the response. Future studies will be directed at characterizing the regulatory protein E2F and understanding how it interacts with the basal transcription complex at the dhfr promoter. The rep-3 gene contains two promoters that are both growth responsive: one promoter is regulated by E2F, the regulator of the other promoter has not been identified. In summary, the in-depth characterization of the 1 kb containing the dhfr and rep-3 promoters has begun to provide a detailed understanding of growth-responsive transcription.