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1 Pulmonary Center and Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA; The Boston VA Healthcare System, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: pkuang{at}lung.bumc.bu.edu.
Elastin, a major extracellular matrix protein and the core component of elastic fiber, is essential to maintain the lung structural integrity and normal physiological function. We previously found that the down-regulation of elastin gene transcription by interleukin (IL)-1
was mediated via activation of NF-
B and the 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 ubiquitin-proteasome pathway using specific proteasome inhibitors. We found that specific proteasome inhibitors decreased the steady-state level of elastin mRNA in a dose-response manner. Run-on assay and promoter reporter study indicated that proteasome inhibitor MG132 repressed the rate of elastin transcription. MG132 did not affect mRNA levels of NF-kB and C/EBP, or the nuclear presence of NF-B, but markedly increased C/EBP isoforms, including liver-enriched transcriptional activator protein (LAP) and liver-enriched transcriptional inhibitory protein (LIP). Addition of cycloheximide blocked these increases and the down-regulation of elastin mRNA by MG132. The MG132-induced down-regulation of elastin transcription was dependent on C/EBP expression as assessed using small interfering RNA (siRNA). 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 down-regulation of tropoelastin transcription via posttranscriptionally- induced C/EBP isoforms.
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