Qiutang Li

NF-κB regulation in the immune system

The nuclear factor-κB (NF-κB)/REL family of transcription factors has a central role in coordinating the expression of a wide variety of genes that control immune responses. There has been intense scientific activity in the NF-κB field owing to the involvement of these factors in the activation and regulation of key molecules that are associated with diseases ranging from inflammation to cancer. In this review, we focus on our current understanding of NF-κB regulation and its role in the immune system and inflammatory diseases. We also discuss the role of NF-κB proteins as potential therapeutic targets in clinical applications.

IkappaB kinase-independent IkappaBalpha degradation pathway: functional NF-kappaB activity and implications for cancer therapy.

ABSTRACT Antiapoptotic activity of NF-κB in tumors contributes to acquisition of resistance to chemotherapy. Degradation of IκB is a seminal step in activation of NF-κB. The IκB kinases, IKK1 and IKK2, have been implicated in both IκB degradation and subsequent modifications of NFκB. Using mouse embryo fibroblasts (MEFs) devoid of both IKK1 and IKK2 genes (IKK1/2−/−), we document a novel IκB degradation mechanism. We show that this degradation induced by a chemotherapeutic agent, doxorubicin (DoxR), does not require the classical serine 32 and 36 phosphorylation or the PEST domain of IκBα. Degradation of IκBα is partially blocked by phosphatidylinositol 3-kinase inhibitor LY294002 and is mediated by the proteasome. Free NF-κB generated by DoxR-induced IκB degradation in IKK1/2−/− cells is able to activate chromatin based NF-κB reporter gene and expression of the endogenous target gene, IκBα. These results also imply that modification of NF-κB by IKK1 or IKK2 either prior or subsequent to its release from IκB is not essential for NF-κB-mediated gene expression at least in response to DNA damage. In addition, DoxR-induced cell death in IKK1/2−/− MEFs is enhanced by simultaneous inhibition of NF-κB activation by blocking the proteasome activity. These results reveal an additional pathway of activating NF-κB during the course of anticancer therapy and provide a mechanistic basis for the observation that proteasome inhibitors could be used as adjuvants in chemotherapy.

Erratum: NF-κB regulation in the immune system

The nuclear factor-κB (NF-κB)/REL family of transcription factors has a central role in coordinating the expression of a wide variety of genes that control immune responses. There has been intense scientific activity in the NF-κB field owing to the involvement of these factors in the activation and regulation of key molecules that are associated with diseases ranging from inflammation to cancer. In this review, we focus on our current understanding of NF-κB regulation and its role in the immune system and inflammatory diseases. We also discuss the role of NF-κB proteins as potential therapeutic targets in clinical applications.

Inhibitors of NF-κB Activity

A part from being a paradigm for understanding cellular signaling, the NF-κB pathway has been thoroughly investigated over the last two decades due to its involvement in a number of human diseases. In the post genomic era, improved knowledge and novel technologies have contributed immensely to the discovery of several hitherto unknown cellular processes that regulate NF-κB. Identification of covalent modifications of many NF-κB pathway components, both in the cytoplasm and the nucleus has shed light on novel mechanisms that regulate NF-κB activity. Similarly, study of a number of cellular and viral proteins that regulate this pathway has added to our understanding of the molecular mechanisms and molecular targets in the NF-κB pathway for drug development.