NF-kB pathways

OTU family DUBs such as Cezanne and A20 also play significant roles as negative regulators of the NE-/cB pathway [43, 44]. A20 can cleave K48- and K63-linked polyubiquitin chains in vitro while Cezanne has only been tested on K48-linked chains. Although these DUBs are known to be part of the NE-/cB pathway, their in vivo substrates are unknown. It is also unclear as to how these DUBs negatively regulate the NE-/cB pathway. 

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Besides direct apoptosis effectors, there are a number of other diugs which influence the above explained apoptosis pathways more indirectly. This class of diugs includes molecules which inhibit survival pathways like e.g. the Ras/Raf kinase pathway, the NF-kB pathway and many others. Also inhibitors of survival cytokines which are sometimes produced by cancer cells in an autocrine fashion can render cells susceptible to apoptosis and, hence, effective cancer therapy. These include, but are not limited to, ligands for dependence receptors and cytokines like e.g. interleukin-4. 

Figure 43-10. Regulation of the NF-kB pathway. NF-kB consists of two subunits, p50 and p65, which regulate transcription of many genes when in the nucleus. NF-kB Is restricted from entering the nucleus by IkB, an Inhibitor of NF-kB. IkB binds to—and masks—the nuclear localization signal of NF-kB.

In the NF-kB pathway with celastrol 76, the inhibition of the iKBa degradation is due to the upstream blockage of the kinase activity and not by the direct inhibition of proteasome activity. On the contrary, direct inhibition of proteasome activity was observed with celastrol 76 and pristimerin 2 in prostate cancer cells.90-92 Both triterpene QMs directly inhibited the activity of the 20S subunits of proteasome at 2.5 iM and induced the accumulation of ubiquitinated proteins over time in cells,... 

IkB kinase-p is a key regulatory enzyme in the NF-kB pathway, and inhibition of this enzyme has the potential for yielding treatments for inflammatory and autoimmune diseases. Morwick et al. [53] report on the optimization of a pM IKKp inhibitor with low aqueous solubility, moderate human liver microsome stability, and inhibition of several CYPs (3A4, 2C9, 1A2) with pM potencies. Modulation of the thiophene core (other thiophene isomer, pyrimidine and oxazole) produces compounds of similar potency to the hit. Fusing the 5-phenyl moiety to the thiophene to form a thieno[2,3-b]pyridine core increases aqueous solubility of the series as well as reduces the CYP liability. While the optimized compound still shows pM IKK(S potency, the aqueous solubility, HLM stability and CYP profiles are much improved. A pharmacophore model was generated that enabled scaffold hopping to yield this new chemotype (Scheme 7). 

Greten, D. and Karin, M. The IKK/NF-kB pathway-a target for prevention and treatment of cancer. Cancer Lett. 206 193-199, 2004. 

Pathway selective ER ligands have been reported that selectively inhibit nuclear factor kB (NF-kB) mediated gene expression [71], Since NF-kB is a pivotal regulator of pro-inflammatory gene expression, ligands that selectively inhibit the NF-kB pathway could be developed for the treatment of chronic inflammatory diseases such as arthritis, atherosclerosis, sepsis, and inflammatory bowel disease... 

A20 mouse severe inflammation, premature death negative regulation of NF-kB pathway [44, 121]... 

The absence of a transactivation-competent NF-kB heterodimer in the nucleus of latently infected resting memory CD4+ T cells could contribute to latency. Activation of the NF-kB pathway leading to migration of a transactivating heterodimer such as p50/p65 could allow viral reactivation. In the absence of induction, NF-kB p50-HDACl complexes constitutively bind the latent HIV-1 LTR (Williams et al, 2006). NF-kB p50 does not possess a transactivation domain. These p50-HDACl complexes induce histone deacetylation and repressive changes in chromatin structure of the HIV-1 LTR (Williams et al, 2006). Knockdown of p50 expression reduces HDACl binding to the latent HIV-1 LTR and induces RNA polymerase II recruitment (Williams et al, 2006). Concomitantly with HIV-1 transcriptional activation, the p65 subunit and different HATs are recruited to the viral promoter (Lusic et al, 2003 Thierry et al, 2004). 

Hiscott J, Kwon H, Genin P. (2001) Hostile takeovers Viral appropriation of the NF-kB pathway. J Clin Invest 107 143-151. 

McDonald PP, Bald A, Cassatella MA. 1997. Activation of the NF-kB pathway by inflammatory stimuli in human PMN. Blood. 89 3421-3433. 

Marchetti L., Klein M., Schlett K., Pfizenmaier K., and Eisel U. L. M. (2004). Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-metliyl-D-aspartate receptor activation-Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kB pathway. J. Biol. Chem. 279 32869-32881. 

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