Abstract
Isothiocyanates (ITCs) are abundantly found in cruciferous vegetables. Epidemiological studies suggest that chronic consumption of cruciferous vegetables can lower the overall risk of cancer. Natural ITCs are key chemopreventive ingredients of cruciferous vegetables, and one of the prime chemopreventive mechanisms of natural isothiocyanates is the induction of Nrf2/ARE-dependent gene expression that plays a critical role in cellular defense against electrophiles and reactive oxygen species. In the present review, we first discuss the underlying mechanisms how natural ITCs affect the intracellular signaling kinase cascades to regulate the Keap1/Nrf2 activities, thereby inducing phase II cytoprotective and detoxifying enzymes. We also discuss the potential cellular protein targets to which natural ITCs are directly conjugated and how these events aid in the chemopreventive effects of natural ITCs. Finally, we discuss the posttranslational modifications of Keap1 and nucleocytoplasmic trafficking of Nrf2 in response to electrophiles and oxidants.
Highlights
carboxyterminal region (CTR) –COOH (b) Kelch-like ECH associating protein 1 (Keap1) Domains oxygen species (ROS), and drug metabolism in response to environmental electrophiles and oxidants [10]
Earlier studies have demonstrated that overexpression of wild-type ERK2 and JNK1 significantly elicited AREdependent luciferase activation and the addition of natural ITCs, including PEITC and sulforaphane, could potentiate the antioxidant response element (ARE)-dependent gene expression, implying that upregulation of Nrf2/ARE-dependent gene expression by natural ITCs is mediated by mitogen-activated protein kinase (MAPK) pathway [25, 26]
While there was a lack of evidence whether Phosphatidylinositol 3-kinase (PI3K) and Akt can directly phosphorylate Keap1 or Nrf2 protein and modulate the activity of ARE-dependent gene expression, Cuadrado and colleagues have demonstrated that active glycogen synthase kinase-3β (GSK3β) can directly phosphorylate and suppress the activity of Nrf2 protein by causing its nuclear exclusion [31]
Summary
Natural Isothiocyanates (ITCs) are abundantly found in cruciferous vegetables such as broccoli, watercress, Brussels sprouts, cabbage, and cauliflower [1]. Exposure of electrophiles and oxidants inactivates Cul3-dependent E3 ubiquitin ligase enzyme in the cytosol by poorly characterized biochemical mechanisms and stabilizes Nrf protein, leading to its nuclear translocation and transcriptional activation by binding to the antioxidant response element (ARE), a cis-acting enhancer sequence TGA(G/C)NNNGC in the genome through heterodimerizing with small Maf proteins [11]. Nrf activity is tightly regulated in the cytosol by Kelch-like ECH associating protein 1 (Keap1) as a scaffolding protein for Nrf as well as an adaptor protein for Cul3-dependent E3 ubiquitin ligase enzyme [12]. The Neh domain contains a basic leucine-zipper (bZIP) structure, required for DNA binding in association with small Maf proteins in the nucleus. The Neh domain is located in the most N-terminal region and exerts a negative effect on the ARE-dependent gene expression by binding to Keap protein. (2) the regulatory mechanism of Nrf and Keap system conforms to the so-called “hinge and latch” model, in which two distinct binding sites in the Neh domain of Nrf protein mediates high-affinity (the ETGE motif) and low-affinity (the DLG motif) interactions with a single Keap protein, respectively [21]
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