Publications
148 results found
Bennett J, Moretti M, Thotakura AK, et al., 2013, The regulation of the JNK cascade and programmed cell death by NF-κB: mechanisms and functions, Trends in Stem Cell Proliferation and Cancer Research, Editors: Resende, Ulrich, Publisher: Springer Netherlands, Pages: 297-336, ISBN: 9789400762107
The nuclear factor κB (NF-κB) family is an evolutionarily conserved family of transcription factors that play a central role in immune and inflammatory responses. They also play a pivotal role in cell survival, whereby activation of NF-κB antagonizes programmed cell death induced by tumor necrosis factor receptors and other cell death signals. The prosurvival function of NF-κB has been implicated in a wide range of biological processes, including the development and homeostasis of the immune system and liver. It has also been implicated in the pathogenesis of numerous diseases, including cancer, chronic inflammation, and certain hereditary disorders. The protective activity of NF-κB can also hamper tumor cell killing inflicted by radiation or chemotherapeutic drugs, thereby promoting resistance to cancer treatments. This prosurvival activity of NF-κB involves the suppression of sustained c-Jun N-terminal kinase (JNK) activation and of the accumulation of cytotoxic reactive oxygen species. NF-κB mediates this function by inducing the transcription of target genes, whose products inhibit the JNK signaling pathway and suppress accumulation of reactive oxygen species through their antioxidant functions. The development of specific inhibitors that target the critical downstream NF-κB-regulated genes that promote survival in cancer and other diseases potentially holds a key to developing specific and effective therapeutic strategies to combat these disorders.
Moretti M, Bennett J, Tornatore L, et al., 2012, Cancer: NF-kappa B regulates energy metabolism, The International Journal of Biochemistry and Cell Biology, Vol: 44, Pages: 2238-2243, ISSN: 1357-2725
NF-κB transcription factors are evolutionarily conserved, central coordinators of immune and inflammatory responses. They also play a pivotal role in oncogenesis. NF-κB exerts these functions by regulating the transcription of genes encoding many immunoregulators, inflammatory mediators and inhibitors of apoptosis. Several studies during the past few years have also underscored the key role of the IKK/NF-κB pathway in the induction and maintenance of the state of inflammation that underlies metabolic pathologies such as obesity, insulin resistance and type-2 diabetes, reflecting the co-evolution and integration of nutrient- and pathogen-sensing systems. Recent reports, however, are revealing an even more intimate, direct connection between NF-κB and metabolism. These studies demonstrate that NF-κB regulates energy homeostasis via direct engagement of the cellular networks governing glycolysis and respiration, with profound implications that extend beyond metabolic pathologies, to cellular physiology, cancer, and anti-cancer therapy. In this review article, we discuss these emerging metabolic functions of NF-κB and their significance to oncogenesis and cancer treatment.
Franzoso G, Tornatore L, Ruvo M, et al., 2012, GADD45BETA as an expression marker useful for the diagnosis, prognosis and theranostics of cancer, WO2012146940A3
A method of measuring Gadd45ß expression comprising the step of measuring Gadd45ß expression levels in a sample of cells, for example CD 138 expressing cells,obtained from a subject known to have or suspected of having a haematological malignancy. Expression levels may be used in diagnosis, for example of multiple myeloma, in providing a prognosis, for example in a patient having multiple myeloma or in guiding selection of an appropriate treatment agent, especially a treatment agent comprising Gadd45ß and or MKK7 inhibitors. Also datasets comprising measured expression levels from multiple subjects.
Mauro C, Leow SC, Anso E, et al., 2012, The Control of Cell Energy Metabolism by NF-Kb Transcription Factors, Transplantation Journal, Vol: 94, Pages: 493-493, ISSN: 0041-1337
Tornatore L, Thotakura AK, Bennett J, et al., 2012, The nuclear factor kappa B signaling pathway: integrating metabolism with inflammation, TRENDS IN CELL BIOLOGY, Vol: 22, Pages: 557-566, ISSN: 0962-8924
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- Citations: 340
Luo Y, Boyle DL, Hammaker D, et al., 2011, Suppression of collagen-induced arthritis in growth arrest and DNA damage-inducible protein 45 beta-deficient mice, Arthritis and Rheumatism, Vol: 63, Pages: 2949-2955, ISSN: 0004-3591
ObjectiveGrowth arrest and DNA damage–inducible protein 45β (GADD45β) is involved in stress responses, cell cycle regulation, and oncogenesis. Previous studies demonstrated that GADD45β deficiency exacerbates K/BxN serum–induced arthritis and experimental allergic encephalomyelitis (EAE) in mice, indicating that GADD45β plays a suppressive role in innate and adaptive immune responses. To further understand how GADD45β regulates autoimmunity, we evaluated collagen-induced arthritis in GADD45β–/– mice.MethodsWild-type (WT) and GADD45β–/– DBA/1 mice were immunized with bovine type II collagen (CII). Serum anticollagen antibody levels were quantified by enzyme-linked immunosorbent assay. Expression of cytokines and matrix metalloproteinases in the joint and spleen was determined by quantitative polymerase chain reaction. The in vitro T cell cytokine response to CII was measured by multiplex analysis. CD4+CD25+ Treg cells and Th17 cells were quantified using flow cytometry.ResultsGADD45β–/– mice showed significantly lower arthritis severity and joint destruction compared with WT mice. MMP-3 and MMP-13 expression was also markedly reduced in GADD45β–/– mice. However, serum anti-CII antibody levels were similar in both groups. FoxP3 and interleukin-10 (IL-10) expression was increased 2–3-fold in splenocytes from arthritic GADD45β–/– mice compared with those from WT mice. Flow cytometric analysis showed greater numbers of CD4+CD25+ Treg cells in the spleen of GADD45β–/– mice than in the spleen of WT mice. In vitro studies showed that interferon-γ and IL-17 production by T cells was significantly decreased in GADD45β–/– mice.ConclusionUnlike passive K/BxN arthritis and EAE, GADD45β deficiency in CIA was associated with lower arthritis severity, elevated IL-10 expression, decreased IL-17 production, and in
Mauro C, Leow SC, Anso E, et al., 2011, NF-kappa B controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration, Nature Cell Biology, Vol: 13, Pages: 1272-U234, ISSN: 1465-7392
Cell proliferation is a metabolically demanding process1,2. It requires active reprogramming of cellular bioenergetic pathways towards glucose metabolism to support anabolic growth1,2. NF-κB/Rel transcription factors coordinate many of the signals that drive proliferation during immunity, inflammation and oncogenesis3, but whether NF-κB regulates the metabolic reprogramming required for cell division during these processes is unknown. Here, we report that NF-κB organizes energy metabolism networks by controlling the balance between the utilization of glycolysis and mitochondrial respiration. NF-κB inhibition causes cellular reprogramming to aerobic glycolysis under basal conditions and induces necrosis on glucose starvation. The metabolic reorganization that results from NF-κB inhibition overcomes the requirement for tumour suppressor mutation in oncogenic transformation and impairs metabolic adaptation in cancer in vivo. This NF-κB-dependent metabolic pathway involves stimulation of oxidative phosphorylation through upregulation of mitochondrial synthesis of cytochrome c oxidase 2 (SCO2; ref. 4). Our findings identify NF-κB as a physiological regulator of mitochondrial respiration and establish a role for NF-κB in metabolic adaptation in normal cells and cancer.
Ma L, Mauro C, Cornish GH, et al., 2010, Ig gene-like molecule CD31 plays a nonredundant role in the regulation of T-cell immunity and tolerance., Proceedings of the National Academy of Sciences of USA, Vol: 107, Pages: 19461-19466, ISSN: 0027-8424
CD31 is an Ig-like molecule expressed by leukocytes and endothelial cells with an established role in the regulation of leukocyte trafficking. Despite genetic deletion of CD31 being associated with exacerbation of T cell-mediated autoimmunity, the contribution of this molecule to T-cell responses is largely unknown. Here we report that tumor and allograft rejection are significantly enhanced in CD31-deficient mice, which are also resistant to tolerance induction. We propose that these effects are dependent on an as yet unrecognized role for CD31-mediated homophilic interactions between T cells and antigen-presenting cells (APCs) during priming. We show that loss of CD31 interactions leads to enhanced primary clonal expansion, increased killing capacity, and diminished regulatory functions by T cells. Immunomodulation by CD31 signals correlates with a partial inhibition of proximal T-cell receptor (TCR) signaling, specifically Zap-70 phosphorylation. However, CD31-deficient mice do not develop autoimmunity due to increased T-cell death following activation, and we show that CD31 triggering induces Erk-mediated prosurvival activity in T cells either in conjunction with TCR signaling or autonomously. We conclude that CD31 functions as a nonredundant comodulator of T-cell responses, which specializes in sizing the ensuing immune response by setting the threshold for T-cell activation and tolerance, while preventing memory T-cell death.
Yang H, Rivera Z, Jube S, et al., 2010, Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 107, Pages: 12611-12616, ISSN: 0027-8424
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- Citations: 202
Svensson CI, Inoue T, Hammaker D, et al., 2009, Gadd45β Deficiency in Rheumatoid Arthritis Enhanced Synovitis Through JNK Signaling, ARTHRITIS AND RHEUMATISM, Vol: 60, Pages: 3229-3240, ISSN: 0004-3591
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- Citations: 30
Franzoso G, 2009, Gadd45β Targeting Agents, WO2011048390A3
Compounds based around tetrapeptide, tripeptide and dipeptide moeties and corresponding peptiod moeties. Related methods and pharmaceutical compositions for use in treatment of cancer, inflammatory diseases, and other disorders.
Papa S, Bubici C, Zazzeroni F, et al., 2009, Mechanisms of liver disease: cross-talk between the NF-kappa B and JNK pathways, 4th International Conference of the Collaborative Research Center 575 Experimental Hepatology (SFB 575), Publisher: De Gruyter, Pages: 965-976, ISSN: 1431-6730
The liver plays a central role in the transformation anddegradation of endogenous and exogenous chemicals,and in the removal of unwanted cells such as damaged,genetically mutated and virus-infected cells. Because ofthis function, the liver is susceptible to toxicity causedby the products generated during these natural occur-rences. Hepatocyte death is the major feature of liverinjury. In response to liver injury, specific intracellularprocesses are initiated to maintain liver integrity. Inflam-matory cytokines including tumor necrosis factor (TNF)aand interleukin-6 (IL-6) are key mediators of these pro-cesses and activate different cellular response such asproliferation, survival and death. TNFainduces specificsignaling pathways in hepatocytes that lead to activationof either pro-survival mediators or effectors of cell death.Whereas activation of transcription factor NF-kBpro-motes survival, c-Jun N-terminal kinases (JNKs) andcaspases are strategic effectors of cell death in theTNFa-mediated signaling pathway. This review summa-rizes recent advances in the mechanisms of TNFa-induced hepatotoxicity and suggests that NF-kB plays aprotective role against JNK-induced hepatocyte death.Identification of the mechanisms regulating interplaybetween the NF-kB and JNK pathways is required in thesearch for novel targets for the treatment of liver disease,including hepatitis and hepatocellular carcinoma.
Papa S, Bubici C, Zazzeroni F, et al., 2009, Mechanisms of liver disease: the crosstalk between the NF-kappaB and JNK pathways., Biological Chemistry: official scientific journal of the GBM, Vol: 390, Pages: 965-976, ISSN: 1431-6730
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 or 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 the liver integrity. Inflammatory cytokines including tumor necrosis factor (TNF)alpha and interleukin-6 (IL-6) are key mediators of these processes as they can activate different cellular response like proliferation, survival and death. TNFalpha induces specific signaling pathways in hepatocytes leading to the activation of either pro-survival mediators or effectors of cell death. While the activation of transcription factor NF-kappaB promotes survival, the induction of c-Jun N-terminal kinases (JNKs) and caspases represent the strategic effectors of cell death in the TNFalpha-mediated signaling pathway. This review summarizes recent advances in the mechanisms of TNFalpha-induced hepatotoxicity, suggesting that NF-kappaB plays a protective role against JNK-induced hepatocyte death. The identification of mechanisms regulating the interplay between the NF-kappaB and JNK pathways is required to identify novel targets for the treatment of liver disease, including hepatitis and hepatocellular carcinoma.
Gilmore TD, Perkins ND, Franzoso G, 2009, Getting away from it all in Capri: the 2008 EMBO workshop on NF-kappa B, Cell Death and Differentiation, Vol: 16, Pages: 651-654, ISSN: 1350-9047
As if seeking refuge from the economic storm circling the globe, approximately 100 researchers gathered amidst the winding paths, massive cliffs, and azure sea on the Isle of Capri, Italy, for an EMBO Workshop on ‘The NF-κB Network in Development and Disease’. Fittingly, the NF-κB signaling pathway is one of the primary regulators of stress and immunity. The meeting featured talks by leading researchers from Europe and the US, two poster sessions and many opportunities for informal conversations and extended questioning.
Tumanov AV, Koroleva EP, Christiansen PA, et al., 2009, T cell-derived lymphotoxin regulates liver regeneration., Gastroenterology, Vol: 136, Pages: 694-704.e4
BACKGROUND & AIMS: The ability of the liver to regenerate hepatic mass is essential to withstanding liver injury. The process of liver regeneration is tightly regulated by distinct signaling cascades involving components of the innate immune system, cytokines, and growth factors. However, the role of the adaptive immune system in regulation of liver regeneration is not well-defined. The role of adaptive immune system in liver regeneration was investigated in lymphocyte-deficient mice and in conditional lymphotoxin-deficient mice. METHODS: A model of liver regeneration after 70% partial hepatectomy was used, followed by examination of liver pathology, survival, DNA synthesis, and cytokine expression. RESULTS: We found that mice deficient in T cells show a reduced capacity for liver regeneration following partial hepatectomy. Furthermore, surface lymphotoxin, provided by T cells, is critical for liver regeneration. Mice specifically deficient in T-cell lymphotoxin had increased liver damage and a reduced capacity to initiate DNA synthesis after partial hepatectomy. Transfer of splenocytes from wild-type but not lymphotoxin-deficient mice improved liver regeneration in T cell-deficient mice. We found that an agonistic antibody against the lymphotoxin beta receptor was able to facilitate liver regeneration by reducing liver injury, increasing interleukin-6 production, hepatocyte DNA synthesis, and survival of lymphocyte-deficient (Rag) mice after partial hepatectomy. CONCLUSIONS: The adaptive immune system directly regulates liver regeneration via a T cell-derived lymphotoxin axis, and pharmacological stimulation of lymphotoxin beta receptor might represent a novel therapeutic approach to improve liver regeneration.
Liu B, Suyeoka G, Papa S, et al., 2009, Growth arrest and DNA damage protein 45b (Gadd45b) protects retinal ganglion cells from injuries, NEUROBIOLOGY OF DISEASE, Vol: 33, Pages: 104-110, ISSN: 0969-9961
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- Citations: 19
Tornatore L, Montil SM, Marasco D, et al., 2009, Gadd45β dimerization does not affect MKK7 binding, 20th American-Peptide-Society Symposium, Publisher: SPRINGER, Pages: 367-368, ISSN: 0065-2598
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- Citations: 1
Mauro C, Zazzeroni F, Papa S, et al., 2009, The NF-κB Transcription Factor Pathway as a Therapeutic Target in Cancer: Methods for Detection of NF-κB Activity, INFLAMMATION AND CANCER: METHODS AND PROTOCOLS, VOL 2: MOLECULAR ANALYSIS AND PATHWAYS, Vol: 512, Pages: 169-207, ISSN: 1064-3745
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- Citations: 39
Tornatore L, Montil SM, Marasco D, et al., 2009, Gadd45beta dimerization does not affect MKK7 binding., Adv Exp Med Biol, Vol: 611, Pages: 367-368, ISSN: 0065-2598
Yang H, Nasu M, Bocchetta M, et al., 2008, Asbestos-induced Human Mesothelial Cell Death Causes the Release of HMGB1 and Resultant Inflammation, 23rd Annual Scientific Meeting of the International-Society-for-Biological-Therapy-of-Cancer, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 932-932, ISSN: 1524-9557
Franzoso G, 2008, Identification of Novel Factors that Block Programmed Cell Death or Apoptosis by Targeting JNK
Yang H, Nasu M, Bocchetta M, et al., 2008, Asbestos-induced human mesothelial cell death causes the release of HMGB1 and resultant inflammation, 3rd International Damage Associated Molecular Pattern Molecules (DAMPs) and Alarmins Symposium, Publisher: FEDERATION AMER SOC EXP BIOL, Pages: A30-A30, ISSN: 0741-5400
Franzoso G, 2008, Identification of Novel Factors that Block Programmed Cell Death or Apoptosis by Targeting JNK, 7,354,898
Tornatore L, Marasco D, Dathan N, et al., 2008, Gadd45{beta} forms a homodimeric complex that binds tightly to MKK7, J Mol Biol, Vol: 378, Pages: 97-111
Franzoso G, 2008, Identification of Novel Factors that Block Programmed Cell Death or Apoptosis by Targeting JNK., 7,326,418
Papa S, Zazzeroni F, Fu YX, et al., 2008, Gadd45{beta} promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling, J Clin Invest, Vol: 118, Pages: 1911-1923
In the liver, the JNK cascade is induced downstream of TNF receptors (TNFRs) in response to inflammatory, microbial, and toxic challenges. Sustained activation of JNK triggers programmed cell death (PCD), and hepatocyte survival during these challenges requires induction of the NF-kappaB pathway, which antagonizes this activation by upregulating target genes. Thus, modulation of JNK activity is crucial to the liver response to TNFR-mediated challenge. The basis for this modulation, however, is unknown. Here, we investigated the role of the NF-kappaB target Gadd45{beta} in the regulation of hepatocyte fate during liver regeneration after partial hepatectomy. We generated Gadd45b(-/-) mice and found that they exhibited decreased hepatocyte proliferation and increased PCD during liver regeneration. Notably, JNK activity was markedly increased and sustained in livers of Gadd45b(-/-) mice compared with control animals after partial hepatectomy. Furthermore, imposition of a Jnk2-null mutation, attenuating JNK activity, completely rescued the regenerative response in Gadd45b(-/-) mice. Interestingly, Gadd45{beta} ablation did not affect hepatotoxic JNK signaling after a TNFR-mediated immune challenge, suggesting specificity in the inducible hepatic program for JNK restraint activated during distinct TNFR-mediated challenges. These data provide a basis for JNK suppression during liver regeneration and identify Gadd45{beta} as a potential therapeutic target in liver diseases.
Tumanov AV, Koroleva EP, Christiansen PA, et al., 2008, T cell derived lymphotoxin regulates liver regeneration, Gastroenterology, Vol: In Press
Centeno C, Repici M, Chatton J-Y, et al., 2007, Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons, CELL DEATH AND DIFFERENTIATION, Vol: 14, Pages: 240-253, ISSN: 1350-9047
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- Citations: 98
Papa S, Monti SM, Vitale RM, et al., 2007, Insights into the structural basis of the Gadd45ß mediated inactivation of the JNK kinase, MKK7, J Chem Biol, Vol: 282, Pages: 19029-19041
NF-B/Rel factors control programmed cell death (PCD), and this control is crucial to oncogenesis, cancer chemoresistance, and antagonism of tumor necrosis factor (TNF) -induced killing. With TNF, NF-B-mediated protection involves suppression of the c-Jun-N-terminal kinase (JNK) cascade, and we have identified Gadd45, a member of the Gadd45 family, as a pivotal effector of this activity of NF-B. Inhibition of TNF-induced JNK signaling by Gadd45 depends on direct targeting of the JNK kinase, MKK7/JNKK2. The mechanism by which Gadd45 blunts MKK7, however, is unknown. Here we show that Gadd45 is a structured protein with a predicted four-stranded -sheet core, five -helices, and two acidic loops. Association of Gadd45 with MKK7 involves a network of interactions mediated by its putative helices 3 and 4 and loops 1 and 2. Whereas 3 appears to primarily mediate docking to MKK7, loop 1 and 4-loop 2 seemingly afford kinase inactivation by engaging the ATP-binding site and causing conformational changes that impede catalytic function. These data provide a basis for Gadd45-mediated blockade of MKK7, and ultimately, TNF-induced PCD. They also have important implications for treatment of widespread diseases.
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