Regulation of the expression of HMG1, a co-activator of the estrogen receptor.

HMG1 is a protein of high clinical significance. Besides shielding of DNA adducts against repair enzymes making cells more sensitive to cisplatin therapy, it is also a co-modulator of the activity of steroid hormone-regulated genes. Although HMG1 is regulated by various factors, including steroid hormone estrogen, nothing was known about regulatory sequences. Also the sequence of parts of HMG1 including its promoter remains still unknown. We have completed the genomic organization of human HMG1 and characterized its regulatory region by luciferase assay for promoter activity. Insights into the regulation of HMG1 expression are given by the promoter analysis showing a strong functional promoter, enhancing and negative regulatory regions together with a CpG island in intron 1 and several transcription factor binding sites. Furthermore, the finding of two estrogen responsive elements within intron 1 is relevant as they indicate a direct mechanism of HMG1 up-regulation by estrogen making the presence of an estrogen receptor a significant marker for a combined treatment of special tumor types with estrogen and the anticancer drugs cisplatin or carboplatin.