Vanadium Interaction with Signal Transduction Cascades as Part of the Therapeutic Effect

2 Vanadium Interaction with Signal Transduction Cascades as Part of the Therapeutic Effect 

Growth hormones, important in diabetes and cancer, activate a receptor with an intrinsic intracellular tyrosine protein kinase activity that passes on the signal by phosphorylating other proteins, often kinases themselves. To date, no specific second messengers have been associated with these systems. The amplification occurs by the turn-on of the receptor-associated protein kinase activity that can phosphorylate many proteins. 

The stress or growth pathways modulated by vanadium involve specialized effectors and often can be activated by excess ROS. Cytokines, small proteins that effect communication between cells or cell behavior, can be involved in the cellular stress response. Tumor necrosis factor a (TNFa) is a cytokine stress signal that binds to a membrane receptor (tumor necrosis factor receptor, or TNFR). This interaction stimulates kinase activity that leads to cell injury and inflammation and also to the activation of caspases, a family of cysteine-dependent aspartate-directed proteases that are involved in apoptosis. The mitogen-activated protein (MAP) kinase cascade regulates both mitosis and apoptosis signaling pathways. 

FIGURE 11.2 Interactions of vanadium with the hormone-sensitive G protein modulated cAMP producing signal transduction system. Bold lines with arrows leading away from V represent stimulation, blunt-ended lines represent inhibition. V shows where vanadium interactions have geen found. Pase phosphatase, PDE(IV) phosphodiesterase (IV), PEPCK phosphoenolpyrurate carboxykinase, PKA, protein kinse A inactive, PKAa PKA active. This figure was adapted from [13]. 

The presence of tumor necrosis factor a directly leads to apoptosis via interaction with the tumor necrosis factor receptor, one of a class of receptors referred to as death receptors. NF-kB, which must enter the nucleus to initiate apoptosis, is a transcription factor sequestered in the cytoplasm by inhibitor of kB (IkB). The binding of TNFa to its receptor leads to the ubiquitin-dependent proteolysis of IkB, allowing NF-kB to enter the nucleus. The activation of apoptosis results directly from the stimulation of NF-kB, a transcription factor whose phosphorylation is controlled by vanadium compounds. In a global gene expression study, it was found that diabetes increased the formation of IkB, whereas vanadium compound treatment lowered the production of this inhibitor [101]. The activation of the TNFR also activates the caspase proteins, a class of proteases that cleave proteins after specific aspartate residues. 

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