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Regulatory elements within the 5′ flanking sequence of the human DR5 gene have consensus sequences for transcription factors such as NF-κB and AP-1 [42]. Activation of NF-κB requires proteosomal degradation of IκB, which involves ubiquitination or other protein modifications of IκB [43]. Since the proteosomal inhibitor MG-132 abrogated H2O2-induced NF-κB activation and subsequent induction of DR5 mRNA expression, proteosomal degradation of IκB seems to play an important role in H2O2-induced NF-κB activation and subsequent DR5 expression.
In previous work, we observed that ROS induced Fas MG-132 by human astroglial cells [26]. Collectively, H2O2 induces Fas and DR5 expression on human astroglial cells, and as a result, astrocytes become sensitized to treatment with TRAIL or FasL, leading to enhanced cell death. Our findings suggest that DR5 expression may be induced by hypoxia/reperfusion and other forms of oxidative stress such as tumor-associated hypoxia. Another important aspect may be chemotherapeutic drug-induced apoptosis of tumor cells because many anticancer drugs produce ROS [44], [45] and [46]. Therefore, oxidative stress leading to up-regulation of DR5 plays a role in apoptosis in pathological conditions of the CNS.