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process that requires both nongenetic and genetic alterations that promote the transformation of normal human cells into highly malignant ones.5 However, currently it is still not clear which step or steps are effectively targeted by metals. Certainly, nuclear factor- kB (NF-kB) activation is involved in the process of carcinogenic transformation of cells, but how metals affect the signal transduction pathways leading to the activation of NF- kB is still poorly understood. It is unequivocal that oxidative stress resulting from metal-induced generation of reactive oxidative species (ROS) is an important mechanism for the activation of NF-kB by metal. However, a ROS-independent effect of metals on the cellular signaling pathway and on genomic stability may also account for

this process.

16.2 SIGNALING PATHWAYS FOR NF-kB ACTIVATION 16.2.1 General Pathway of NF-kB Activation

A wide range of signals, which typically include cytokines, mitogens, environmental and occupational particles or metals, intracellular stresses, viral and bacterial products, and ultraviolet (UV) radiation, induce expression of early response genes via the NF-kB family of transcription factors.8'9 In resting cells, NF-kB is sequestered in the cytoplasm of most cells where it is bound to a family of inhibitory proteins, such as IKBa, IkB^, IkBe, p105, and p100. Activation of the NF-kB signaling cascade results in complete degradation of IkB or the carboxy terminal partial degradation of the p105 and p100 precursors, allowing nuclear translocation of the NF-kB complexes (Figure 16.1). Activated NF-kB binds to specific DNA sequences in target genes, designated as KB-elements, and regulates transcription of genes mediating inflammation, carcinogenesis, and antiapoptotic reactions.

IKBa is the most abundant inhibitory protein for NF-kB.9 The mechanisms of signal-induced IKBa degradation involve phosphorylation of two serine residues, S32 and S36. This phosphorylation leads to polyubiquitination of two specific lysines on IKBa (K21 and K22) by the SCF-/i-TrCP complex and its degradation by the 26S proteasome.10 The phosphorylation is accomplished by a specific IkB kinase (IKK) complex containing two catalytic subunits, IKKa and IKK/i, and a structural component named NEMO/IKK 7/IKKAP.11'12 IKKa and IKK/i share a 50% sequence similarity. Both proteins contain an amino terminal kinase domain, a carboxy terminal region with a leucine zipper, and a helix-loop-helix domain. In vitro or in vivo studies indicate that both IKKa and IKK^ are capable of phosphorylating IKBa on ser32 and ser36, but IKK/i is more potent in IKBa phosphorylation induced by proinflammatory stimuli. Recent studies by several groups indicate the existence of an additional IKK-like kinase complex in T cells, named IKKi/e,13'14 which shares 27% homology with IKKa and IKK/i and possibly mediates NF-KB-activating kinase (NAK) signaling and PMA/PKCe-induced S36 phosphorylation of IKBa and NF-kB activation.

Diverse stimuli, with a possible exception of UV, activate NF-kB through activation of the kinase activity of IKK that phosphorylate IkBs, a critical step required for subsequent ubiquitination and degradation. UV-induced NF-kB activation may be via a mechanism that does not depend on IKK or N-terminal phosphorylation of IkB.15'16 It is known that the activity of IKK can be stimulated by TNFa, IL-1, LPS, Tax protein, ionizing radiation, vanadate, and double-stranded RNA. However, how these diverse stimuli activate IKK remains elusive. A number of kinases, mostly based on transient overexpression in which wild-type forms activate IKK and catalytically inactive forms inhibit IKK, have been suggested to be able to phosphorylate and activate IKK. These kinases include MEKK1,17 NIK,11 TBK1/NAK,14,18 Akt,19,20 PKC0,21'22 PKC£23 Cot kinase,24 PKR,25 and MLK3.26 It is not clear whether each of these upstream kinases represents one of many routes to IKK activation by specific stimuli or represents a ubiquitous mediator leading the activation of IKK induced by diverse stimuli.

Activation Ros

FIGURE 16.1 Signaling pathways of NF-kB activation. A number of extracellular stress inducers, including cytokines, ROS, the viral or bacterial products, stimulate IKK through upstream kinases directly or indirectly. Activated IKK phosphorylates N-terminal S32 and S36 residues of IKBa that is associated with the NF-kB p50 and p65 heterodimer. The SCF-yS-TrCP complex recognizes phosphorylated IKBa and modifies IKBa with polyubiquitin chains. This is followed by proteasome-mediated degradation of IKBa. After degradation of IKBa, the activated NF-kB translocates into the nucleus, where it binds to the KB-sites of gene promoters or enhancers to upregulate target gene expression. Line arrows and filled arrows denote the NF-kB signaling pathways; open arrows denote the connections with bystanding signaling pathways.

FIGURE 16.1 Signaling pathways of NF-kB activation. A number of extracellular stress inducers, including cytokines, ROS, the viral or bacterial products, stimulate IKK through upstream kinases directly or indirectly. Activated IKK phosphorylates N-terminal S32 and S36 residues of IKBa that is associated with the NF-kB p50 and p65 heterodimer. The SCF-yS-TrCP complex recognizes phosphorylated IKBa and modifies IKBa with polyubiquitin chains. This is followed by proteasome-mediated degradation of IKBa. After degradation of IKBa, the activated NF-kB translocates into the nucleus, where it binds to the KB-sites of gene promoters or enhancers to upregulate target gene expression. Line arrows and filled arrows denote the NF-kB signaling pathways; open arrows denote the connections with bystanding signaling pathways.

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