Francesca Zazzeroni

Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling.

In addition to coordinating immune and inflammatory responses, NF-κB/Rel transcription factors control cell survival. Normally, NF-κB dimers are sequestered in the cytoplasm by binding to inhibitory IκB proteins, and can be activated rapidly by signals that induce the sequential phosphorylation and proteolysis of IκBs. Activation of NF-κB antagonizes apoptosis or programmed cell death by numerous triggers, including the ligand engagement of ‘death receptors’ such as tumour-necrosis factor (TNF) receptor. The anti-apoptotic activity of NF-κB is also crucial to oncogenesis and to chemo- and radio-resistance in cancer. Cytoprotection by NF-κB involves the activation of pro-survival genes; however, its basis remains poorly understood. Here we report that NF-κB complexes downregulate the c-Jun amino-terminal kinase (JNK) cascade, thus establishing a link between the NF-κB and the JNK pathways. This link involves the transcriptional upregulation of gadd45β/myd118 (ref. 4), which downregulates JNK signalling induced by the TNF receptor (TNF-R). This NF-κB-dependent inhibition of the JNK pathway is central to the control of cell death. Our findings define a protective mechanism that is mediated by NF-κB complexes and establish a role for the persistent activation of JNK in the apoptotic response to TNF-α.

Ferritin Heavy Chain Upregulation by NF-κB Inhibits TNFα-Induced Apoptosis by Suppressing Reactive Oxygen Species

Abstract During inflammation, NF-κB transcription factors antagonize apoptosis induced by tumor necrosis factor (TNF)α. This antiapoptotic activity of NF-κB involves suppressing the accumulation of reactive oxygen species (ROS) and controlling the activation of the c-Jun N-terminal kinase (JNK) cascade. However, the mechanism(s) by which NF-κB inhibits ROS accumulation is unclear. We identify ferritin heavy chain (FHC)—the primary iron storage factor—as an essential mediator of the antioxidant and protective activities of NF-κB. FHC is induced downstream of NF-κB and is required to prevent sustained JNK activation and, thereby, apoptosis triggered by TNFα. FHC-mediated inhibition of JNK signaling depends on suppressing ROS accumulation and is achieved through iron sequestration. These findings establish a basis for the NF-κB-mediated control of ROS induction and identify a mechanism by which NF-κB suppresses proapoptotic JNK signaling. Our results suggest modulation of FHC or, more broadly, of iron metabolism as a potential approach for anti-inflammatory therapy.

Gadd45|[beta]| mediates the NF-|[kappa]|B suppression of JNK signalling by targeting MKK7/JNKK2

NF-κB/Rel transcription factors control apoptosis, also known as programmed cell death. This control is crucial for oncogenesis, cancer chemo-resistance and for antagonizing tumour necrosis factor α (TNFα)-induced killing. With regard to TNFα, the anti-apoptotic activity of NF-κB involves suppression of the c-Jun N-terminal kinase (JNK) cascade. Using an unbiased screen, we have previously identified Gadd45β/Myd118, a member of the Gadd45 family of inducible factors, as a pivotal mediator of this suppressive activity of NF-κB. However, the mechanisms by which Gadd45β inhibits JNK signalling are not understood. Here, we identify MKK7/JNKK2 — a specific and essential activator of JNK — as a target of Gadd45β, and in fact, of NF-κB itself. Gadd45β binds to MKK7 directly and blocks its catalytic activity, thereby providing a molecular link between the NF-κB and JNK pathways. Importantly, Gadd45β is required to antagonize TNFα-induced cytotoxicity, and peptides disrupting the Gadd45β/MKK7 interaction hinder the ability of Gadd45β, as well as of NF-κB, to suppress this cytotoxicity. These findings establish a basis for the NF-κB control of JNK activation and identify MKK7 as a potential target for anti-inflammatory and anti-cancer therapy.

Linking JNK signaling to NF-κB: a key to survival

In addition to marshalling immune and inflammatory responses, transcription factors of the NF-κB family control cell survival. This control is crucial to a wide range of biological processes, including B and T lymphopoiesis, adaptive immunity, oncogenesis and cancer chemoresistance. During an inflammatory response, NF-κB activation antagonizes apoptosis induced by tumor necrosis factor (TNF)-α, a protective activity that involves suppression of the Jun N-terminal kinase (JNK) cascade. This suppression can involve upregulation of the Gadd45-family member Gadd45β/Myd118, which associates with the JNK kinase MKK7/JNKK2 and blocks its catalytic activity. Upregulation of XIAP, A20 and blockers of reactive oxygen species (ROS) appear to be important additional means by which NF-κB blunts JNK signaling. These recent findings might open up entirely new avenues for therapeutic intervention in chronic inflammatory diseases and certain cancers; indeed, the Gadd45β-MKK7 interaction might be a key target for such intervention.

The NF-κB-mediated control of the JNK cascade in the antagonism of programmed cell death in health and disease

NF-κB/Rel transcription factors have recently emerged as crucial regulators of cell survival. Activation of NF-κB antagonizes programmed cell death (PCD) induced by tumor necrosis factor-receptors (TNF-Rs) and several other triggers. This prosurvival activity of NF-κB participates in a wide range of biological processes, including immunity, lymphopoiesis and development. It is also crucial for pathogenesis of various cancers, chronic inflammation and certain hereditary disorders. This participation of NF-κB in survival signaling often involves an antagonism of PCD triggered by TNF-R-family receptors, and is mediated through a suppression of the formation of reactive oxygen species (ROS) and a control of sustained activation of the Jun-N-terminal kinase (JNK) cascade. Effectors of this antagonistic activity of NF-κB on this ROS/JNK pathway have been recently identified. Indeed, further delineating the mechanisms by which NF-κB promotes cell survival might hold the key to developing new highly effective therapies for treatment of widespread human diseases.

The Inflammatory Microenvironment in Hepatocellular Carcinoma: A Pivotal Role for Tumor-Associated Macrophages

Hepatocellular carcinoma (HCC) is one of the most common and aggressive human cancers worldwide. HCC is an example of inflammation-related cancer and represents a paradigm of the relation occurring between tumor microenvironment and tumor development. Tumor-associated macrophages (TAMs) are a major component of leukocyte infiltrate of tumors and play a pivotal role in tumor progression of inflammation-related cancer, including HCC. Several studies indicate that, in the tumor microenvironment, TAMs acquire an M2-polarized phenotype and promote angiogenesis, metastasis, and suppression of adaptive immunity through the expression of cytokines, chemokines, growth factors, and matrix metalloproteases. Indeed, an established M2 macrophage population has been associated with poor prognosis in HCC. The molecular links that connect cancer cells and TAMs are not completely known, but recent studies have demonstrated that NF-κB, STAT-3, and HIF-1 signaling pathways play key roles in this crosstalk. In this paper, we discuss the current knowledge about the role of TAMs in HCC development, highlighting the role of TAM-derived cytokines, chemokines, and growth factors in the initiation and progression of liver cancer and outlining the signaling pathways involved in the interplay between cancer cells and TAMs.

Upregulation of Twist-1 by NF-κB Blocks Cytotoxicity Induced by Chemotherapeutic Drugs

ABSTRACT NF-κB/Rel transcription factors are central to controlling programmed cell death (PCD). Activation of NF-κB blocks PCD induced by numerous triggers, including ligand engagement of tumor necrosis factor receptor (TNF-R) family receptors. The protective activity of NF-κB is also crucial for oncogenesis and cancer chemoresistance. Downstream of TNF-Rs, this activity of NF-κB has been linked to the suppression of reactive oxygen species and the c-Jun-N-terminal-kinase (JNK) cascade. The mechanism by which NF-κB inhibits PCD triggered by chemotherapeutic drugs, however, remains poorly understood. To understand this mechanism, we sought to identify unrecognized protective genes that are regulated by NF-κB. Using an unbiased screen, we identified the basic-helix-loop-helix factor Twist-1 as a new mediator of the protective function of NF-κB. Twist-1 is an evolutionarily conserved target of NF-κB, blocks PCD induced by chemotherapeutic drugs and TNF-α in NF-κB-deficient cells, and is essential to counter this PCD in cancer cells. The protective activity of Twist-1 seemingly halts PCD independently of interference with cytotoxic JNK, p53, and p19ARF signaling, suggesting that it mediates a novel protective mechanism activated by NF-κB. Indeed, our data indicate that this activity involves a control of inhibitory Bcl-2 phosphorylation. The data also suggest that Twist-1 and -2 play an important role in NF-κB-dependent chemoresistance.

NF-κB protects from the lysosomal pathway of cell death

The programme of gene expression induced by RelA/NF‐κB transcription factors is critical to the control of cell survival. Ligation of ‘death receptors’ such as tumor necrosis factor receptor 1 (TNF‐R1) triggers apoptosis, as well as NF‐κB, which counteracts this process by activating the transcription of anti‐apoptotic genes. In addition to activating caspases, TNF‐R1 stimulation causes the release of cathepsins, most notably cathepsin B, from the lysosome into the cytoplasm where they induce apoptosis. Here we report a mechanism by which NF‐κB protects cells against TNF‐α‐induced apoptosis: inhibition of the lysosomal pathway of apoptosis. NF‐κB can protect cells from death after TNF‐R1 stimulation, by extinguishing cathepsin B activity in the cytosol. This activity of NF‐κB is mediated, at least in part, by the upregulation of Serine protease inhibitor 2A (Spi2A), a potent inhibitor of cathepsin B. Indeed, Spi2A can substitute for NF‐κB in suppressing the induction of cathepsin B activity in the cytosol. Thus, inhibition of cathepsin B by Spi2A is a mechanism by which NF‐κB protects cells from lysosome‐mediated apoptosis.

NF-κB and JNK: An Intricate Affair

NF-κB/Rel transcription factors block apoptosis or programmed cell death (PCD)induced by tumor necrosis factor (TNF)α. The antiapoptotic activity of NF-κB is alsocrucial for immunity, lymphocyte development, tumorigenesis, and cancerchemoresistance. With respect to TNF?, the NF-κB-mediated suppression of apoptosisinvolves inhibition of the c-Jun-N-terminal kinase (JNK) cascade. This inhibitory activityof NF-κB depends upon transcriptional upregulation of blockers of the JNK cascade suchas the caspase inhibitor XIAP, the zinc-finger protein A20, and the inhibitor of theMKK7/JNKK2 kinase Gadd45β/Myd118. Moreover, NF-κB blunts accumulation ofreactive oxygen species (ROS) induced by TNF?, and this antioxidant effect of NF-κB isalso critical for inhibition of TNFα-induced JNK activation. Suppression of ROS by NF-κB is mediated by Ferritin heavy chain (FHC)—the primary iron-storage mechanism incells—and possibly, by the mitochondrial enzyme Mn++ superoxide dismutase (Mn-SOD). Thus, induction of FHC and Mn-SOD represents an additional, indirect means bywhich NF-κB controls proapoptotic JNK signaling. These findings identify potential newtargets for anti-inflammatory and anti-cancer therapy.

Mechanisms of liver disease: cross-talk between the NF-kappaB and JNK pathways.

Abstract The liver plays a central role in the transformation and degradation of endogenous and exogenous chemicals, and in the removal of unwanted cells such as damaged, genetically mutated and virus-infected cells. Because of this function, the liver is susceptible to toxicity caused by the products generated during these natural occurrences. Hepatocyte death is the major feature of liver injury. In response to liver injury, specific intracellular processes are initiated to maintain liver integrity. Inflammatory cytokines including tumor necrosis factor (TNF)α and interleukin-6 (IL-6) are key mediators of these processes and activate different cellular response such as proliferation, survival and death. TNFα induces specific signaling pathways in hepatocytes that lead to activation of either pro-survival mediators or effectors of cell death. Whereas activation of transcription factor NF-κB promotes survival, c-Jun N-terminal kinases (JNKs) and caspases are strategic effectors of cell death in the TNFα-mediated signaling pathway. This review summarizes recent advances in the mechanisms of TNFα-induced hepatotoxicity and suggests that NF-κB plays a protective role against JNK-induced hepatocyte death. Identification of the mechanisms regulating interplay between the NF-κB and JNK pathways is required in the search for novel targets for the treatment of liver disease, including hepatitis and hepatocellular carcinoma.