Molecular mechanisms involved in enhancing HO-1 expression: de-repression by heme and activation by Nrf2, the "one-two" punch.

Heme oxygenase (HO)-1 is a stress response protein, which confers cytoprotection against oxidative injury and provides a vital function in maintaining tissue homeostasis. Molecular mechanisms involved in the inducible transcription of ho-1 occurring in response to numerous and diverse stressful conditions have remained elusive. Since the discovery of E1 and E2, the two upstream enhancers regulating induction of ho-1 transcription in 1989, there have been many studies dealing with molecular mechanisms involved in enhancing HO-1 expression. In this commentary, recent advances in our understanding of the mechanisms involved in the induction of HO-1 expression in mammalian cells are summarized with some supportive results reported by others. Currently available data indicate that activation of ho-1 transcription involves both the heme (native substrate)-dependent selective alleviation of repressor and the oxidative stress-dependent activation of transcriptional activator. The stress-released free-heme (HO-1 substrate) from hemoproteins involved in causing oxidative stress itself appears to act as a molecular switch controlling the repressor- activator antagonism on the enhancer sequences of ho-1. Thus, induction of HO-1 appears to operate in a manner like a simple feedback loop. dox Signal. 7, 1674-1687.