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 NF-KappaB (p50 p65) pathway

The NF-KappaB family is composed of homo- and heterodimers of Rel proteins; NF-KappaB1 (p50); NF-KappaB2 (p52), RelA (p65), RelB, and c-Rel (Rel). NF-KappaB (p50/p65) is a ubiquitous, constitutive and inducible heterodimer. The general term NF-KappaB traditionally refers to the p50/p65 (p50/RelA) heterodimer, which is an anti-apoptotic gene regulator. The p65 (RelA) subunit provides the gene regulatory function. NFkappaB is retained in the cytoplasm complexed with IkappaBs, such as IkappaBalpha (IKBα). The IkappaBkinase complex (IKK) is an immediate upstream effector containing either IKKα or IKKβ kinase that phosphorylates IkBα or IkBβ when activated by Akt/PKB, receptor interacting protein (RIP) or other upstream kinases. Phosphorylated IkappaBs are degraded by the ubiquitin-proteosome and the free NFkappaB heterodimer translocates to the nucleus.

In the nucleus, the p65 NF-kappaB subunit is a strong activator for a wide variety of genes. p65 gene activator activity is regulated by post-translational modifications; phosphorylation and acetylation. Kinases such as protein kinase A catalytic subunit (PKAc), mitogen- and stress-activated kinase 1 (MSK1), casein kinase-II (CSKN-II) and IKK differentially phosphorylate p65 in response to signaling events. Phosphorylated p65 interacts with kB-DNA, and co-activators such as CREB-binding protein (CBP) and p300, acetyltransferases, to promote specific gene activation. A complex balance of acetylation and deacetylation events determines the promotion, strength and duration of gene activation by p65. P65 eventually releases from the DNA and binds to newly synthesized IkBalpha. The IKBα:NFkappaB (p50/p65) complex translocates back to the cytoplasm.