Structure and function of the HMGI(Y) family of architectural transcription factors

The three known members of the HMGI(Y) family of high-mobility group (HMG) mammalian nonhistone nuclear proteins (HMG-I, HMG-Y, and HMGI-C) are though t to participate in numerous biological processes (transcription, replicati on, retroviral integration, genetic recombination, etc.) by virtue of their ability to recognize and alter the structure of both DNA and chromatin sub strates. In vitro and in vivo the HMGI(Y) proteins preferentially bind to t he narrow minor groove of stretches of AT-rich DNA by means of highly conse rved peptide motifs called AT hooks. In vitro the HMGI(Y) proteins also hav e the ability to selectively bind to distorted DNA structures and to bend, unwind, and supercoil DNA substrates. Additionally, the HMGI(Y) proteins ha ve the ability to interact with various protein transcription factors both in vitro and in vivo. Specific protein-DNA and protein-protein interactions permit the HMGI(Y) proteins to function as architectural transcription fac tors that regulate gene expression in vivo by controlling the formation of stereospecific multiprotein complexes on the AT-rich regions of certain gen e promoters. Transcriptional overexpression of the HMGI(Y) genes is highly correlated with both cancerous transformation and increased metastatic pote ntial of a number of different cancers, and chromosomal rearrangements invo lving AT-hook motifs have been associated with various types of benign huma n mesenchymal tumors. The levels of HMGI(Y) proteins in human cells have be en proposed to be sensitive diagnostic indicators of both neoplastic transf ormation and metastatic progression. Drugs based on the AT-hook motif offer the potential for development of new tumor therapeutic reagents.