Transcriptional regulation via cysteine thiol modification: A novel molecular strategy for chemoprevention and cytoprotection

Abstract

Chemoprevention refers to the use of defined nontoxic chemical regimens to inhibit, reverse, or retard the process of multistage carcinogenesis that involves multiple signal transduction events. Identification of signaling molecules associated with carcinogenesis as prime targets of chemopreventive agents has become an area of great interest. Recent studies have implicated cysteine thiols present in various transcription factors, such as NF-kappaB, AP-1, and p53 as redox sensors in transcriptional regulation of many genes essential for maintaining cellular homeostasis. Some chemopreventive and cytoprotective agents have been found to target cysteine thiols present in key transcription factors or their regulators, thereby suppressing aberrant over-activation of carcinogenic signal transduction or restoring/normalizing or even potentiating cellular defense signaling. The focus of this review is the oxidation or covalent modification of thiol groups present in key representative redox-sensitive transcription factors and their regulating molecules as a unique strategy for molecular target-based chemoprevention and cytoprotection.

Nrf2 regulates an adaptive response protecting against oxidative damage following diquat-mediated formation of superoxide anion

“…Although several redox-sensitive transcription factors, such as nuclear factor-κB and activating protein 1, influence the development of oxidative diseases [45,46], our study clearly illustrated the role of Nrf2 in regulating an adaptive response leading to protection against ROS. The results of this and other studies demonstrate that an Nrf2-mediated adaptive antioxidative response represents an effective innate mechanism protecting organisms against oxidative stress.…”

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

“…In addition to redox control through oxidation of kinases and phosphatases, molecular adaptors, or chaperones, that can in turn regulate the activity of transcription factors, transcription factors themselves can also be direct targets of redox control, a topic that has been extensively reviewed [192]. Perhaps the first evidence for this was based upon the work on the bacterial transcription factor OxyR which was demonstrated to be directly activated by oxidants via the formation of a reversible disulfide bond [193][194][195] (Figure 2, box 5).…”

Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway

“…Nitric oxide (NO)-mediated S-nitrosylation can inhibit p50 DNAbinding activity through modification of Cys-62 (Matthews et al, 1996) (Figure 3; Table 3). Indeed, modification of reactive cysteine residues provides a mechanism through which several oxidizing agents, natural products and natural product derivatives can inhibit both IKK and NF-kB subunits (Straus et al, 2000;Kwok et al, 2001;Garcia-Pineres et al, 2004;Park et al, 2005a;Liang et al, 2006c;Na and Surh, 2006). Interestingly, epoxyquinone A inhibits RelA DNAbinding activity through Cys-38 modification, the equivalent of p50 Cys-62 (Liang et al, 2006b).…”