Regulation of heme oxygenase-1 gene transcription: Recent advances and highlights from the International Conference (Uppsala, 2003) on heme oxygenase

Recent investigations into the regulation of heme oxygenase-1 gene (hmox-1) transcription have exposed mechanisms of increasing diversity and complexity worthy of a gene whose expression is modulated by a seemingly endless array of physiological, pathophysiological, and nonphysiological agents and conditions. For instance, contrary to initial and prevalent assumptions that inducer-dependent gene stimulation is mediated principally by the positive action of transcription activators, it now appears that such induction may occur secondarily to deactivation of the repressor protein, Bach1. As a further complication, heme and cadmium, two potent inducers of the hmox-1 gene, inhibit Bach1 function by different mechanisms-by inhibition of DNA binding or promotion of nuclear export, respectively. Bach1 also plays a role in signal-dependent hmox-1 gene repression, an increasingly appreciated phenomenon that is manifested in a species- and cell-specific manner. Although extreme concentrations of the heme oxygenase-1 protein resulting from the opposing phenomena of gene activation and repression have physiological consequences, even minor modulation in the level of this enzyme, as elicited by variations in the length of a dinucleotide repeat region within the human hmox-1 promoter, may be of clinical relevance. Finally, mechanistic diversity is also apparent in the type and combination of protein kinase-dependent, signal transduction pathways used during hmox-1 gene activation.