Nuclear translocation Phosphorylation

Fig. 2.2 Simplified scheme of oxidant/antioxidant regulation ofNF-KB activation. Different stimuli, leading to an increase of ROS generation inside the ceU, activate the phosphorylation of IkB inhibitory protein and the subsequent proteolysis. Thioredoxin (Trx) may reduce activated NF-kB proteins facilitating nuclear translocation.Qnce released from IkB, the NF-kB complex translocates into the nucleus and the binding to DNA domain in the promoters and enhancers of genes such as TNF-a, IL-1, proliferation and chemotactic factors, adhesion molecule. Some of these genes, in turn, may further induce NF-kB activation, leading to a vicious circle if the regulatory cellular system escapes from...

The phosphorylation state of the transcription factor NF-AT has a different effect on translocation. The phosphorylated form of this protein is localized in the cytosol and requires dephosphorylation by the protein phosphatase calcineiuln in order to be translocated to the nucleus (see also 7.5.2). Other examples for phosphorylation-dependent nuclear translocation include the STAT-proteins (see 11.1.3.2) and the SMAD-proteins (see 12.1.2). 

Khokhlatchev, A.V., Canagarajah, B., Wilsbacher, J., Robinson, M., Atkinson, M., Goldsmith, E. and Cobb, M.H. Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation (1998) Cell 93, 605-615... 

Apopa PL, He X, Ma Q. 2008. Phosphorylation of Nrf2 in the transcription activation domain by casein kinase 2 (CK2) is critical for the nuclear translocation and transcription activation function of Nrf2 in IMR-32 neuroblastoma cells. J Biochem Mol Toxicol 22 63-76. 

NF-/< B is stimulated by multiple stimuli within stressed cells of different origin to form part of a protective response (Baichwal and Baeuerle, 1997) (Table 7.3). Upon stimulation LB is rapidly phosphorylated, ubiquinated, and then degraded by proteasomes resulting in the release and subsequent nuclear translocation of active NF-/cB. 

A major signalling pathway involves activation of a protein kinase that phosphorylates inhibitor kB proteins (IkBs) that normally inhibit the function of the nuclear transcription factor NFkB. Phosphorylation of IkB by the serine/threonine-specific IkB kinases (IKKs) leads to NFkB de-inhibition, nuclear translocation and expression of pro-inflammatory proteins such as inducible cyclooxygenase (iCOX) (which generates prostaglandins), inducible nitric oxide synthase (iNOS) (which generates vasodilatory and toxic free radicalgenerating NO) and pro-inflammatory cytokines. 

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