Michael Karin

Immunity, inflammation, and cancer.

Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis. Inflammation also affects immune surveillance and responses to therapy. Immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells, and some of the molecular events that mediate this dialog have been revealed. This review outlines the principal mechanisms that govern the effects of inflammation and immunity on tumor development and discusses attractive new targets for cancer therapy and prevention.

Mammalian MAP kinase signalling cascades

Mitogen-activated protein kinases (MAPKs) are important signal transducing enzymes, unique to eukaryotes, that are involved in many facets of cellular regulation. Initial research concentrated on defining the components and organization of MAPK signalling cascades, but recent studies have begun to shed light on the physiological functions of these cascades in the control of gene expression, cell proliferation and programmed cell death.

Missing Pieces in the NF-κB Puzzle

The regulation of the transcription factor NF-kappaB activity occurs at several levels including controlled cytoplasmic-nuclear shuttling and modulation of its transcriptional activity. A critical component in NF-kappaB regulation is the IkappaB kinase (IKK) complex. This review is focused on recent progress as well as unanswered questions regarding the regulation and function of NF-kappaB and IKK.

A central role for JNK in obesity and insulin resistance

Obesity is closely associated with insulin resistance and establishes the leading risk factor for type 2 diabetes mellitus, yet the molecular mechanisms of this association are poorly understood. The c-Jun amino-terminal kinases (JNKs) can interfere with insulin action in cultured cells and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes. Here we show that JNK activity is abnormally elevated in obesity. Furthermore, an absence of JNK1 results in decreased adiposity, significantly improved insulin sensitivity and enhanced insulin receptor signalling capacity in two different models of mouse obesity. Thus, JNK is a crucial mediator of obesity and insulin resistance and a potential target for therapeutics.

AP-1 function and regulation.

AP-1 (activating protein-1) is a collective term referring to dimeric transcription factors composed of Jun, Fos or ATF (activating transcription factor) subunits that bind to a common DNA site, the AP-1-binding site. As the complexity of our knowledge of AP-1 factors has increased, our understanding of their physiological function has decreased. This trend, however, is beginning to be reversed due to the recent studies of gene-knockout mice and cell lines deficient in specific AP-1 components. Such studies suggest that different AP-1 factors may regulate different target genes and thus execute distinct biological functions. Also, the involvement of AP-1 factors in functions such as cell proliferation and survival has been made somewhat clearer as a result of such studies. In addition, there has been considerable progress in understanding some of the mechanisms and signaling pathways involved in the regulation of AP-1 activity. In addition to regulation by heterodimerization between Jun, Fos and ATF proteins, AP-1 activity is regulated through interactions with specific protein kinases and a variety of transcriptional coactivators.

NF-κB at the crossroads of life and death

The choice between life and death is one of the major events in regulation of the immune system. T cells that specifically recognize viral or bacterial antigens are selected to survive and proliferate in response to infection, whereas those that are self-reactive are eliminated via apoptosis. Even the survival of alloreactive T cells requires their proper costimulation and, when infection subsides, the activated T cells are eliminated. A major regulator of such life or death decisions is the transcription factor NF-κB. However, NF-κB cannot function alone. A variety of mechanisms exist to modulate its activity and thereby affect the ultimate outcome of a cells fate.

NF-kappaB: linking inflammation and immunity to cancer development and progression.

There has been much effort recently to probe the long-recognized relationship between the pathological processes of infection, inflammation and cancer. For example, epidemiological studies have shown that ∼15% of human deaths from cancer are associated with chronic viral or bacterial infections. This Review focuses on the molecular mechanisms that connect infection, inflammation and cancer, and it puts forward the hypothesis that activation of nuclear factor-κB (NF-κB) by the classical, IKK-β (inhibitor-of-NF-κB kinase-β)-dependent pathway is a crucial mediator of inflammation-induced tumour growth and progression, as well as an important modulator of tumour surveillance and rejection.

NF-κB in cancer: from innocent bystander to major culprit

Nuclear factor of κB (NF-κB) is a sequence-specific transcription factor that is known to be involved in the inflammatory and innate immune responses. Although the importance of NF-κB in immunity is undisputed, recent evidence indicates that NF-κB and the signalling pathways that are involved in its activation are also important for tumour development. NF-κB should therefore receive as much attention from cancer researchers as it has already from immunologists.

Immunosuppression by Glucocorticoids: Inhibition of NF-κB Activity Through Induction of IκB Synthesis

Glucocorticoids are among the most potent anti-inflammatory and immunosuppressive agents. They inhibit synthesis of almost all known cytokines and of several cell surface molecules required for immune function, but the mechanism underlying this activity has been unclear. Here it is shown that glucocorticoids are potent inhibitors of nuclear factor kappa B (NF-κB) activation in mice and cultured cells. This inhibition is mediated by induction of the IκBα inhibitory protein, which traps activated NF-κB in inactive cytoplasmic complexes. Because NF-κB activates many immunoregulatory genes in response to pro-inflammatory stimuli, the inhibition of its activity can be a major component of the anti-inflammatory activity of glucocorticoids.

Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor

The promoter regions of several phorbol diester-(TPA-) inducible genes (collagenase, stromelysin, hMT IIA, and SV40) share a conserved 9 bp motif. Synthetic copies of these closely related sequences conferred TPA inducibility upon heterologous promoters. Footprinting analysis indicated that these TPA-responsive elements (TREs) are recognized by a common cellular protein: the previously described transcription factor AP-1. A point mutation that eliminated the basal and induced activity of the TRE also interfered with its ability to bind AP-1. Treatment of cultured cells with TPA led to a rapid 3- to 4-fold increase in TRE binding activity, by a posttranslational mechanism. These results strongly suggest that AP-1 is at the receiving end of a complex pathway responsible for transmitting the effects of phorbol ester tumor promoters from the plasma membrane to the transcriptional machinery.