IKK and IKK catalytic subunits and the IKK? regulatory subunit is activated, resulting in I?B phosphorylation and eventual ubiquitinmediated degradation, leading to the nuclear entry of freed NF ?B dimmers. Of the two catalytic subunits, IKK is the one which is most critical for I?B degradation, forming the core of what is known as AT7519 the classical NF ?B activation pathway. By contrast, IKK is required for the inducible processing of the inactive p100 protein to its active derivative p52, thus forming the core of the so called alternative NF ?B pathway. A link between NF ?B and cancer first became evident with the cloning of RelA and the realization of its close kinship with the viral oncoprotein v Rel. The view was further supported by observations of activated NF ?B in many human cancers.
In addition, the Bcl 3 oncogene, activated by chromosomal translocation in B cell chronic lymphocytic leukemia, was identified as a member of the I?B family. More recently, mutations in upstream components of the IKK NF ?B signaling system were identified in multiple myeloma and are thought to lead to cell  autonomous activation of NF ?B, thereby enhancing cell survival and proliferation. However, extensive search failed to identify NF ?B activating mutations in most other cancers and most likely cancer associated constitutive NF ?B activities Bergenin are the result of exposure to pro inflammatory stimuli in the tumor microenvironment. Hepatocyte IKK dependent NF ?B signaling suppresses liver cancer development by promoting hepatocyte survival A key role of NF ?B in liver homeostasis was first revealed by studying RelA/p65 deficient mice, which suffer embryonic lethality with extensive liver apoptosis and degeneration.
This liver apoptosis is induced by TNF and backcrossing of p65 knockout mice with TNFor TNF receptor 1 deficient mice prevents liver damage and the lethal phenotype. Later on, IKK and IKK? knockout mice were found to exhibit very similar phenotypes. These genetic studies clearly demonstrate an anti apoptotic role for IKK dependent NF ?B signaling in hepatocytes, mainly during early liver development. The role of IKK dependent classical NF ?B signaling in adult mouse liver physiology, however, is more complex. Mice with hepatocytes specific ablation of IKK develop normally and their livers are not even sensitive to administration of LPS, a strong TNF inducer.
However, careful analysis suggests that residual hepatocyte IKK activity in Ikk?hep mice may be sufficient for TNF induced NF ?B activation, which is completely blocked by an additional ablation of IKK. These results suggest that IKK and IKK in adult hepatocytes may have somewhat redundant functions in suppressing apoptosis and necrosis. Indeed, unlike Ikk?hep mice, Ikk/Ikk?hep mice or mice deficient of the regulatory component IKK? in hepatocytes suffer from extensive hepatocyte death and liver failure upon TNF inducing challenges. Furthermore, Ikk??hep or Ikk/Ikk?hep mice exhibit spontaneous liver damage, which is not seen in Ikk?hep mice. Like Ikk?hep mice, mice deleted of RelA in hepatocytes are also healthy unless challenged and exposed to TNF. Based on available evidence, it is safe to conclude that the IKK/NF ?B pathway is important for hepatocyte survival and maintenance of liv