High mobility group A2 protein and its derivatives bind a specific region of the promoter of DNA repair gene ERCC1 and modulate its activity.

High mobility group A2 (HMGA2) chromosomal non-histone protein and its derivatives play an important role in development and progression of benign and malignant tumors, obesity and arteriosclerosis, although the underlying mechanisms of these conditions are poorly understood. Therefore, we tried to identify target genes for this transcriptional regulator and to provide insights in the mechanism of interaction to its target. Multiple genes have been identified by microarray experiments as being transcriptionally regulated by HMGA2.

Human HMGA2 promoter is coregulated by a polymorphic dinucleotide (TC)-repeat.

HMGA proteins are thought to be causally involved in the progression of different diseases, including benign and malignant tumors, obesity, arteriosclerosis, and restenosis. As HMGA proteins are architectural transcription factors, their binding to DNA leads to changes in DNA-conformation modulating the environment for the assembly and function of transcriptional complexes, thus influencing the expression of a huge variety of genes. Despite the emerging role of HMGA proteins for important diseases, only limited information is available about mechanisms regulating the expression of the HMGA2 gene.

Variation of HMGB1 expression in breast cancer.

The amount of steroid hormone receptor proteins does not always correlate with the response of breast cancers to endocrine therapy. This may partly be due to the fact that binding of the estrogen receptor (ER) to estrogen responsive elements (ERE) of its target genes is mediated by additional cellular proteins. One of these is the high mobility group protein HMGB1, known to interact with ER thus dramatically increasing its binding to ERE.

The expression of HMGA genes is regulated by their 3'UTR.

Many benign mesenchymal tumors are characterized by chromosomal abnormalities of the regions 12q15 or 6p21.3 leading to aberrant expression of either HMGA2 (formerly HMGIC) or HMGA1 (formerly HMGIY). The proteins of both genes belong to the HMGA (formerly HMGI(Y)) family of architectural transcription factors.

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.