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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Regulation of elastin gene transcription by proteasome dysfunction

Pulmonary Center and Department of Biochemistry, Boston University School of Medicine, Boston Department of Veterans Affairs Healthcare System, Boston, Massachusetts

Submitted 27 October 2004 ; accepted in final form 30 March 2005

ABSTRACT

Elastin, a major extracellular matrix protein and the core component of elastic fiber, is essential to maintain lung structural integrity and normal physiological function. We previously found that the downregulation of elastin gene transcription by IL-1 is mediated via activation of NF-B and CCAAT/enhancer binding protein (C/EBP), both targets of the ubiquitin-proteasome pathway. To further investigate the molecular mechanisms that underlie the control of elastin gene expression, we disrupted the ubiquitin-proteasome pathway with specific proteasome inhibitors. We found that specific proteasome inhibitors decreased the steady-state level of elastin mRNA in a dose-responsive manner. Run-on assay and promoter reporter study indicated that the proteasome inhibitor MG-132 repressed the rate of elastin transcription. MG-132 did not affect mRNA levels of NF-B and C/EBP, or the nuclear presence of NF-B, but markedly increased C/EBP isoforms, including liver-enriched transcriptional activating protein and liver-enriched transcriptional inhibitory protein. Addition of cycloheximide blocked these increases and the downregulation of elastin mRNA by MG-132. The MG-132-induced downregulation of elastin transcription was dependent on C/EBP expression as assessed with small interfering RNA. These results indicate that the ubiquitin-proteasome pathway plays an essential role in maintaining elastin gene expression in lung fibroblasts. Disruption of this pathway results in the downregulation of tropoelastin transcription via posttranscriptionally induced C/EBP isoforms.

interleukin-1; lung; fibroblasts; nuclear factor-B; CCAAT/enhancer-binding protein

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