Proteasome inhibitors up-regulate haem oxygenase-1 gene expression: requirement of p38 MAPK (mitogen-activated protein kinase) activation but not of NF-kappaB (nuclear factor kappaB) inhibition

Abstract

Regulation of intracellular protein stability by the ubiquitin-dependent proteasome system plays a crucial role in cell function. HO-1 (haem oxygenase) is a stress response protein, which confers cytoprotection against oxidative injury and provides a vital function in maintaining tissue homoeostasis. In the present study, we found a novel action of proteasome inhibitors MG132 and MG262 on HO-1 induction, and characterized the underlying mechanisms. MG132 (> or =0.1 microM) treatment resulted in a marked time- and concentration-dependent induction of the steady-state level of HO-1 mRNA in RAW264.7 macrophages, followed by a corresponding increase in HO-1 protein. Actinomycin D and cycloheximide inhibited MG132-responsive HO-1 protein expression, indicating a requirement for transcription and de novo protein synthesis. The involvement of signal pathways in MG132-induced HO-1 gene expression was examined using chemical inhibitors. Antioxidant N -acetylcysteine and SB203580, an antioxidant and inhibitor of p38 MAPK (mitogen-activated protein kinase), abolished MG132-inducible HO-1 expression. Furthermore, MG132 activated the p38 MAPK pathway. The half-life of HO-1 protein was prolonged by MG132, indicating that the upregulation of HO-1 by proteasome inhibitor is partially attributable to the inhibition of protein degradation. MG132 can ablate IkappaBalpha degradation and NF-kappaB (nuclear factor kappaB) activation induced by lipopolysaccharide, similar to the effect of another NF-kappaB inhibitor pyrrolidine dithiocarbamate. We found HO-1 upregulation by MG132 and pyrrolidine dithiocarbamate is unrelated to their inhibition of NF-kappaB, since leptomycin B, another NF-kappaB inhibitor, did not elicit similar induction of HO-1. Taken together, we found a novel effect of proteasome inhibitor on induction of HO-1 expression. This action is ascribed to the activation of the p38 MAPK pathway, but is not dependent on NF-kappaB inhibition.

An IκBα phosphorylation inhibitor induces heme oxygenase-1(HO-1) expression through the activation of reactive oxygen species (ROS)–Nrf2–ARE signaling and ROS–PI3K/Akt signaling in an NF-κB-independent mechanism

“…Furthermore, this paper also reported that PDTC, another NF-κB inhibitor, increases HO-1 expression. Like MG132, PDTC induces HO-1 expression via AP-1 signaling [45]. In our studies, Bay activates p38 MAPK signaling, but this signaling was not involved in Bay-induced HO-1 expression (Fig.…”

“…Although these three NF-κB inhibitors use different mechanisms, all can efficiently inhibit NF-κB signaling. Recently, other group reported that MG132 induced HO-1 expression in Raw 264.7 macrophage cells [45]. Wu et al suggested that MG132 increases HO-1 expression through activation of p38 MAPK-AP-1 signaling and partial stabilization of HO-1 protein and that this phenomenon was independent of NF-κB signaling.…”

Epithelial-derived Fibronectin Expression, Signaling, and Function in Intestinal Inflammation

“…Pathway-To determine the role of FN-induced NF-B in cell attachment, Caco2-BBE cells were exposed to FN in the presence or absence of NF-B inhibitors MG-132 (29) or ADTC (30). As shown in Fig.…”

Proteasome inhibitor MG-132 induces C6 glioma cell apoptosis via oxidative stress

“…Therefore, oxidative stress could cause cell death via apoptotic pathways. Several studies have shown that oxidative stress is closely associated with the proteasome, as the proteasome is involved in regulating anti-oxidants, including catalase, heme oxygenase-1 (HO-1), copper/zinc-superoxide dismutase and γ-GCS [11][12][13][14] . However, the relationship between proteasome dysfunction and oxidative stress is still a matter of dispute.…”