Summary
During the past few years, my efforts have been directed towards the identification and characterization of the downstream effectors of the prosurvival activity of NF-kappaB. My primary focus was to uncover a mechanism by which Gadd45β, a downstream effector of NF-kappaB, blunts JNK signalling. We have identified the MAPKK MKK7/JNKK2 – a specific and essential activator of JNK – as a target of Gadd45{beta}, and in fact, of NF-kappaB itself. Gadd45{beta} associates directly and tightly with MKK7, inhibiting its catalytic activity, and this inhibition is central to the Gadd45b-mediated suppression of TNF-induced JNK signalling and apoptosis (Papa S. et al., Nat Cell Biol, 2004). Subsequently, we have defined the precise mechanism by whichGadd45{beta} blocks MKK7, and ultimately, TNF-induced programmed cell death (Papa S. et al., J Biol Chem, 2007). These findings identify the MKK7-Gadd45{beta} interaction as a potential new target for anti-inflammatory and anti-cancer therapy. Interestingly, pharmacological compounds that disrupt Gadd45{beta} binding to MKK7 might uncouple anti-apoptotic and proinflammatory functions of NF-kappaB, and so, circumvent the potent immunosuppressive side effects of global blockers of NF-kappaB.
To understand the physiological contexts in which Gadd45{beta} blocks the JNK activity, I then generated and analyzed Gadd45{beta}-null mice. Analyses of these mice revealed that Gadd45{beta} is required for liver regeneration, and the regenerative response is associated with selective attenuation of JNK2 isoform. These findings have important implications for treatment of widespread liver diseases (Papa S. et al., J Clin Invest, 2008; Papa S. et al., Biol Chem. 2009).
After completing my research training at University of Chicago and Imperial College London, I've been appointed at the Institute of Hepatology London as Group Leader while continuing to teach and supervise MSc and BSc students at Imperial College.
Since 2016, I have joined the Leeds Institute of Medical Research at University of Leeds to lead the Cell Signaling and Cancer group. The focus of our research is to understand the molecular mechanisms, regulation and role of apoptosis (i.e. programmed cell death) in the pathogenesis of human conditions, and translating these insights in therapeutic concepts and novel treatments for diseases including cancer, inflammation and infectious disease.
Fo more updated informations visit my lab website
Selected Publications
Journal Articles
Lepore A, Choy PM, Lee NC, et al., 2021, Phosphorylation and stabilization of PIN1 by JNK promote intrahepatic cholangiocarcinoma growth, Hepatology, Vol:74, ISSN:0270-9139, Pages:2561-2579
Papa S, Bubici C, Syn W-K, 2021, STARD1: a new rising StAR in cholesterol-mediated hepatocarcinogenesis, Hepatobiliary Surgery and Nutrition, Vol:10, ISSN:2304-3881
Arif E, Wang C, Swiderska-Syn MK, et al., 2021, Targeting myosin 1c inhibits murine hepatic fibrogenesis, American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol:320, ISSN:0193-1857, Pages:G1044-G105
Bubici C, Lepore A, Papa S, 2019, ASKing no more: the emerging role of DUSP12 in the regulation of hepatic lipid metabolism, Hepatology, Vol:70, ISSN:0270-9139, Pages:1091-1094
Bubici C, Papa S, 2019, Editorial: The warburg effect regulation under siege: the intertwined pathways in health and disease, Frontiers in Cell and Developmental Biology, Vol:7, ISSN:2296-634X
Papa S, Choy PM, Bubici C, 2019, The ERK and JNK pathways in the regulation of metabolic reprogramming, Oncogene, Vol:38, ISSN:0950-9232, Pages:2223-2240
Lee NCW, Carella MA, Papa S, et al., 2018, High expression of glycolytic genes in cirrhosis correlates with the risk of developing liver cancer, Frontiers in Cell and Developmental Biology, Vol:6, ISSN:2296-634X
Papa S, Bubici C, 2018, Feeding the hedgehog: a new meaning for JNK signalling in liver regeneration, Journal of Hepatology, Vol:69, ISSN:0168-8278, Pages:572-574
Manka P, Coombes JD, Boosman R, et al., 2018, Thyroid hormone in the regulation of hepatocellular carcinoma and its microenvironment, Cancer Letters, Vol:419, ISSN:0304-3835, Pages:175-186
Verzella D, Bennett J, Fischietti M, et al., 2018, GADD45β loss ablates innate immunosuppression in cancer, Cancer Research, Vol:78, ISSN:1538-7445, Pages:1275-1292
Papa S, Bubici C, 2016, Linking apoptosis to cancer metabolism: Another missing piece of JuNK, Molecular & Cellular Oncology, Vol:3, ISSN:2372-3556
Iansante V, Choy PM, Fung SW, et al., 2015, PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation, Nature Communications, Vol:6, ISSN:2041-1723
Coombes JD, Swiderska-Syn M, Dollé L, et al., 2015, Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice, Gut, Vol:64, Pages:1120-1131
Bubici C, Papa S, 2014, JNK signalling in cancer: in need of new, smarter therapeutic targets, British Journal of Pharmacology, Vol:171, ISSN:0007-1188, Pages:24-37
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, ISSN:0950-9232, Pages:4231-4242
Svensson CI, Inoue T, Hammaker D, et al., 2009, Gadd45β Deficiency in Rheumatoid Arthritis Enhanced Synovitis Through JNK Signaling, Arthritis and Rheumatism, Vol:60, ISSN:0004-3591, Pages:3229-3240
Papa S, Bubici C, Zazzeroni F, et al., 2009, Mechanisms of liver disease: the crosstalk between the NF-kappaB and JNK pathways., Biological Chemistry, Vol:390, ISSN:1431-6730, Pages:965-976
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
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
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
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, ISSN:0950-9232, Pages:6731-6748
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, ISSN:1350-9047, Pages:712-729
Pham CG, Bubici C, Zazzeroni F, et al., 2004, Ferritin heavy chain upregulation by NF-κB inhibits TNFα-induced apoptosis by suppressing reactive oxygen species, Cell, Vol:119, ISSN:0092-8674, Pages:529-542
Papa S, Zazzeroni F, Pham CG, et al., 2004, Linking JNK signaling to NF-κB:: a key to survival, Journal of Cell Science, Vol:117, ISSN:0021-9533, Pages:5197-5208
Papa S, Zazzeroni F, Bubici C, et al., 2004, Gadd45{beta} mediates the NF-kappaB suppression of JNK signalling by targeting MKK7/JNKK2., Nat. Cell Biol., Vol:6, Pages:146-153
Zazzeroni F, Papa S, De Smaele E, et al., 2003, Cell signalling (communication arising) - Cell survival and a Gadd45-factor deficiency - Reply, Nature, Vol:424, ISSN:0028-0836, Pages:742-742
De Smaele E, Zazzeroni F, Papa S, et al., 2001, Induction of <i>gadd45β</i> by NF-κB downregulates pro-apoptotic JNK signalling, Nature, Vol:414, ISSN:0028-0836, Pages:308-313
Conference
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), BMJ PUBLISHING GROUP, Pages:A416-A416, ISSN:0017-5749