Zinc mesoporphyrin induces rapid and marked degradation of the transcription factor Bach1 and up-regulates HO-1.

Abstract

Heme oxygenase 1 (HO-1) is the first and rate-controlling enzyme in heme degradation. Bach1 is a mammalian transcriptional repressor of HO-1. To understand how zinc mesoporphyrin (ZnMP) induces the expression of HO-1, we investigated the effects of ZnMP on Bach1 mRNA and protein levels in human hepatoma Huh-7 cells by quantitative RT-PCR and Western blots. We found that ZnMP markedly up-regulated HO-1 mRNA and protein levels, and rapidly and significantly decreased Bach1 protein levels by increasing degradation of Bach1 protein [half life (t(1/2)) from 19 h to 45 min], whereas ZnMP did not influence Bach1 mRNA levels. The proteasome inhibitors, epoxomicin and MG132, significantly inhibited degradation of Bach1 by ZnMP in a dose-dependent fashion, indicating that the degradation of Bach1 by ZnMP is proteasome-dependent. Purified Bach1 C-terminal fragment bound heme, but there was no evidence for binding of ZnMP to the heme-binding region of Bach1. In conclusion, ZnMP produces profound post-transcriptional down-regulation of Bach1 protein levels and transcriptional up-regulation of HO-1. Our results indicate that ZnMP up-regulates HO-1 gene expression by markedly increasing Bach1 protein degradation in a proteasome-dependent manner.

• Authors: Weihong Hou, Ying Shan, Jianyu Zheng, Richard W Lambrecht, Susan E Donohue, Herbert L Bonkovsky
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1779 Issue 3 Pg. 195-203 (Mar 2008) ISSN: 0006-3002 [Print] Netherlands
• PMID: 18325350 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• BACH1 protein, human
• Basic-Leucine Zipper Transcription Factors
• Fanconi Anemia Complementation Group Proteins
• Leupeptins
• Metalloporphyrins
• Oligopeptides
• RNA, Messenger
• Recombinant Proteins
• Heme
• zinc mesoporphyrin
• Heme Oxygenase-1
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde
• epoxomicin

Topics

• Basic-Leucine Zipper Transcription Factors (genetics, metabolism)
• Cell Line, Tumor
• Fanconi Anemia Complementation Group Proteins (genetics, metabolism)
• Gene Expression Regulation, Enzymologic
• Heme (metabolism)
• Heme Oxygenase-1 (metabolism)
• Humans
• Leupeptins (pharmacology)
• Metalloporphyrins (pharmacology)
• Oligopeptides (pharmacology)
• Protein Binding
• RNA, Messenger (metabolism)
• Recombinant Proteins (metabolism)
• Up-Regulation