Publications
71 results found
Coombes J, Claridge LC, Swiderska-Syn M, et al., 2013, Osteopontin enhances liver progenitor cell responses in progressive Nonalcoholic Steatohepatitis, 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases, Publisher: WILEY-BLACKWELL, Pages: 535A-535A, ISSN: 0270-9139
Barbarulo A, Iansante V, Chaidos A, et al., 2013, Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma, Oncogene, Vol: 32, Pages: 4231-4242, ISSN: 0950-9232
Regulation of cell survival is a key part of the pathogenesis of multiple myeloma (MM). Jun N-terminal kinase (JNK) signaling has been implicated in MM pathogenesis, but its function is unclear. To elucidate the role of JNK in MM, we evaluated the specific functions of the two major JNK proteins, JNK1 and JNK2. We show here that JNK2 is constitutively activated in a panel of MM cell lines and primary tumors. Using loss-of-function studies, we demonstrate that JNK2 is required for the survival of myeloma cells and constitutively suppresses JNK1-mediated apoptosis by affecting expression of poly(ADP-ribose) polymerase (PARP)14, a key regulator of B-cell survival. Strikingly, we found that PARP14 is highly expressed in myeloma plasma cells and associated with disease progression and poor survival. Overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown, indicating that PARP14 is critically involved in JNK2-dependent survival. Mechanistically, PARP14 was found to promote the survival of myeloma cells by binding and inhibiting JNK1. Moreover, inhibition of PARP14 enhances the sensitization of MM cells to anti-myeloma agents. Our findings reveal a novel regulatory pathway in myeloma cells through which JNK2 signals cell survival via PARP14, and identify PARP14 as a potential therapeutic target in myeloma.
Iansante V, Zen Y, Barbarulo A, et al., 2012, MAPK SIGNALLING REGULATES THE DEVELOPMENT OF A CHOLANGIOCELLULAR PHENOTYPE FROM HCC IN POST-TACE LIVER TRANSPLANTS, 1st Combined Digestive Disorders Federation Meeting of the British-Society-of-Gastroenterology (BSG), Association-of-Upper-Gastrointestinal-Surgeons (AUGIS), BAPEN and British-Association-for-the-Study-of-the-Liver (BASL), Publisher: BMJ PUBLISHING GROUP, Pages: A416-A416, ISSN: 0017-5749
Iansante V, Zen Y, Barbarulo A, et al., 2012, MIXED-PHENOTYPE HEPATOCELLULAR CARCINOMA IN LIVER TRANSPLANTS AFTER USE OF TRANSARTERIAL CHEMOEMBOLIZATION (TACE) IS ASSOCIATED WITH ACTIVATION OF MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) SIGNALLING PATHWAY, International Liver Congress / 47th Annual Meeting of the European-Association-for-the-Study-of-the-Liver (EASL), Publisher: ELSEVIER SCIENCE BV, Pages: S117-S117, ISSN: 0168-8278
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
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.
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
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, 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
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
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
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.
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.
Kuntzen C, Zazzeroni F, Pham CG, et al., 2007, A method for isolating prosurvival targets of NF-κB/Rel transcription factors., Methods Mol. Biol., Vol: 399, Pages: 99-124
Pham CG, Bubici C, Zazzeroni F, et al., 2007, Upregulation of Twist-1 by NF-kB blocks cytotoxicity induced by chemotherapeutic drugs, Mol Cell Biol, Vol: 27, Pages: 3920-3935
NF-B/Rel transcription factors are central to controlling programmed cell death (PCD). Activation of NF-B blocks PCD induced by numerous triggers, including ligand engagement of tumor necrosis factor receptor (TNF-R) family receptors. The protective activity of NF-B is also crucial for oncogenesis and cancer chemoresistance. Downstream of TNF-Rs, this activity of NF-B has been linked to the suppression of reactive oxygen species and the c-Jun-N-terminal-kinase (JNK) cascade. The mechanism by which NF-B 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-B. Using an unbiased screen, we identified the basic-helix-loop-helix factor Twist-1 as a new mediator of the protective function of NF-B. Twist-1 is an evolutionarily conserved target of NF-B, blocks PCD induced by chemotherapeutic drugs and TNF- in NF-B-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-B. 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-B-dependent chemoresistance.
Tornatore L, Monti SM, Marasco D, et al., 2007, Gadd45β dimerization does not affect MKK7 bindi ng, 20th American-Peptide-Society Symposium, Publisher: JOHN WILEY & SONS INC, Pages: 635-635, ISSN: 0006-3525
Bubici C, Papa S, Dean K, et al., 2006, Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance, ONCOGENE, Vol: 25, Pages: 6731-6748, ISSN: 0950-9232
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- Citations: 340
Larsen CM, Dossing MG, Papa S, et al., 2006, Growth arrest- and DNA-damage-inducible 45β gene inhibits c-Jun N-terminal kinase and extracellular signal-regulated kinase and decreases IL-1β-induced apoptosis in insulin-producing INS-1E cells, DIABETOLOGIA, Vol: 49, Pages: 980-989, ISSN: 0012-186X
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- Citations: 31
Papa S, Bubici C, Zazzeroni F, et al., 2006, The NF-κB-mediated control of the JNK cascade in the antagonism of programmed cell death in health and disease, CELL DEATH AND DIFFERENTIATION, Vol: 13, Pages: 712-729, ISSN: 1350-9047
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- Citations: 188
Mittal A, Papa S, Franzoso G, et al., 2006, NF-κB-dependent regulation of the timing of activation-induced cell death of T lymphocytes, JOURNAL OF IMMUNOLOGY, Vol: 176, Pages: 2183-2189, ISSN: 0022-1767
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- Citations: 35
Bubici C, Papa S, Pham CG, et al., 2006, The NF-κB-mediated control of ROS and JNK signaling, Histology and Histopathology, Vol: 21, Pages: 69-80, ISSN: 0213-3911
NF-κB/Rel transcription factors are best known for their roles in innate and adaptive immunity and inflammation. They also play a central role in promoting cell survival. This latter activity of NF-κB antagonizes programmed cell death (PCD) induced by the proinflammatory cytokine tumor necrosis factor (TNF)α and plays an important role in immunity, lymphopoiesis, osteogenesis, tumorigenesis and radio- and chemo-resistance in cancer. With regard to TNFα, the NF-κB-mediated inhibition of PCD seems to involve an attenuation of the c-Jun-N-terminal kinase (JNK) cascade mediated through the induction of select downstream targets such as the caspase inhibitor XIAP, the zinc-finger protein A20, and the inhibitor of the MKK7/JNKK2 kinase, Gadd45β/Myd118. Notably, NF-κB also blunts accumulation of reactive oxygen species (ROS), which themselves are pivotal elements for induction of PCD by TNFα, and this suppression of ROS formation mediates an additional protective activity recently ascribed to NF-κB. The antioxidant activity of NF-κB has been shown to depend upon upregulation of both Ferritin heavy chain (FHC) - a component of Ferritin, the primary iron-storage protein complex found in cells - and of the mitochondrial enzyme Mn++ superoxide dismutase (Mn-SOD). Indeed, the inductions of Mn-SOD and FHC represent another important means through which NF-κB controls proapoptotic JNK signaling triggered by TNFα. These findings might enable the development of new, more targeted approaches to treatment of diseases sustained by a deregulated activity of NF-κB, including some cancers and chronic inflammatory conditions.
Bubici C, Papa S, Pham CG, et al., 2006, The NF-κB-mediated control of ROS and JNK signaling, HISTOLOGY AND HISTOPATHOLOGY, Vol: 21, Pages: 69-80, ISSN: 0213-3911
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- Citations: 151
Mittal A, Papa A, Franzoso G, et al., 2006, NF-κB-dependent regulation of the timing of activation induced cell death of T lymphocytes., J. Immunol., Vol: 176, Pages: 2183-2189
Papa S, Bubici C, Pham CG, et al., 2005, NF-κB meets ROS:: an 'ron-ic' encounter, CELL DEATH AND DIFFERENTIATION, Vol: 12, Pages: 1259-1262, ISSN: 1350-9047
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- Citations: 21
Pham CG, Papa S, Bubici C, et al., 2005, Oxygen JNKies: Phosphatases overdose on ROS, DEVELOPMENTAL CELL, Vol: 8, Pages: 452-454, ISSN: 1534-5807
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- Citations: 14
Pham CG, Papa S, Bubici C, et al., 2005, In the crosshairs: NF-κB targets the JNK signaling cascade., Curr. Med. Chem. - AIAA, Vol: 4, Pages: 569-576
Bubici C, Papa S, Pham CG, et al., 2004, NF-κB and JNK -: An intricate affair, CELL CYCLE, Vol: 3, Pages: 1524-1529, ISSN: 1538-4101
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- Citations: 88
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