Cadmium Induces Nuclear Export of Bach1, a Transcriptional Repressor of Heme Oxygenase-1 Gene

Abstract

The export of certain nuclear proteins is involved in the regulation of various nuclear functions, including transcription. In some cases, the export of target proteins is induced upon environmental or cellular cues, resulting in conditional gene expression. The small Maf proteins appear to be critical regulators of heme oxygenase (HO)-1, an anti-oxidant defense enzyme that degrades heme into iron, carbon monoxide, and biliverdin. Although ho-1 is repressed by Bach1/small Maf heterodimers, it is activated by Nrf2/small Maf heterodimers, indicating that Bach1 and Nrf2 compete with each other. We anticipated that the nuclear concentration of Bach1 might be regulated to ensure that the entire system effectively responds to various stimuli. We carried out detailed domain analysis of Bach1 in an effort to understand how various inducers of HO-1 inactivate Bach1. We show here that cadmium, a strong inducer of HO-1, activates the nuclear export of Bach1. This cadmium-induced export of Bach1 was mediated in trans by its C-terminal region that is conserved between Bach1 and Bach2. The nuclear export of Bach2 was also induced by cadmium, indicating that the cadmium responsibility is shared between Bach1 and Bach2. The nuclear export of Bach1 was dependent on Crm1/Exportin-1 as well as the extracellular signal-regulated kinase-1/2 (ERK1/2) activity. These results indicate that the nuclear export of Bach1 constitutes an important regulatory mechanism to relieve the Bach1-mediated repression of genes such as ho-1.

Heme: a versatile signaling molecule controlling the activities of diverse regulators ranging from transcription factors to MAP kinases

“…No single HRM (CP) motif is indispensable for heme regulation of Bach1, indicating that there is functional redundancy among the HRM (CP) motifs [22]. The three heme binding motifs of Bach1 function as heme-activated nuclear export signals, suggesting that Bach1-mediated gene expression is at least partially mediated by the regulation of Bach1 subcellular localization [77,83,84].…”

Bach1-dependent and -independent Regulation of Heme Oxygenase-1 in Keratinocytes

“…MafF, MafG, and MafK), which bind the Maf recognition element (MARE) in the promoter regions of genes such as HO-1, NADP(H) quinone (oxido)reductase, and ␤-globin (7,9,10), and thereby repress transcription in the absence of oxidative stress. In the presence of oxidative stress, Bach1 is inactivated (11,12), which allows transcriptional activation of these genes by Nrf2 and other activators that also form heterodimers with small Maf proteins (7,13). Thus, redox regulation is partly mediated by reciprocal DNA-MARE binding by the Bach1 repressor and other transcriptional activators.…”

Redox-regulated Turnover of Nrf2 Is Determined by at Least Two Separate Protein Domains, the Redox-sensitive Neh2 Degron and the Redox-insensitive Neh6 Degron

“…The existence of functionally distinct bZIP dimers allows the cell to control ARE-driven gene transcription by varying the quantity of specific cnc and small Maf proteins in the nucleus and, therefore, the spectrum of dimers expressed. Accordingly, cellular adaptation to oxidative stress involves, among other changes, a rapid increase in the nuclear level of Nrf2 (13)(14)(15), possibly coupled with a decrease in the amount of Bach1 (16), leading in turn to enhanced recruitment of Nrf2-containing dimers to the promoters of ARE-regulated genes (17).…”