SERGE Y. FUCHS
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Ryan Hospital Philadelphia, PA
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SERGE Y. FUCHS, Ph.D., M.D.

Professor of Cell Biology, Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine

Director, Mari Lowe Center for Comparative Oncology, University of Pennsylvania School of Veterinary Medicine

Research Areas: Autoimmune diseases, Cytokines and Grown factors, Interferon, Ubiquitin, Cancer
PubMed Link
Contact Information:
316 Hill Veterinary School
380 S. University Ave

Research Interests
Aberrations of cytokine receptors ubiquitination and degradation in cancer, inflammation and autoimmune diseases

Key words: interferon, receptor, ubiquitin, ligase, cancer, inflammation, cytokine, signal transduction

Description of Research
Protein mediators of intercellular signaling (cytokines and growth factors) ensure a collective behavior of cells within a tissue via binding to their cognate receptors and triggering complex programs of signal transduction and transcriptional regulation. Responsiveness of cells to these protein regulators depend on the cell surface levels of receptors that rapidly undergo ubiquitination and downregulation in response to ligands as well as other intra- and extracellular stimuli. These signaling processes leading to cell de-sensitization collectively termed “ELIMINATIVE SIGNALING” are the focus of our studies. The long-term objective our laboratory is to identify the aberrations in eliminative signaling of cytokine/growth factor receptors that are critical to development of cancers, and responses to infections and autoimmune processes. For our studies, we employ various approaches and methods of molecular and cellular biology, biochemistry and mammalian genetics.

Main research area: Eliminative signaling by interferons (IFN) and proteolysis of the interferon alpha receptor (IFNAR). This receptor plays an essential role in anti-tumorigenic, anti-viral and immunomodulatory effects of Type I IFN, which are often used in therapy of cancers, chronic viral infections and multiple sclerosis. Enzymatic regulators of IFNAR fate include specific protein kinases, phosphatases, E3 ubiquititin ligases and de-ubiquitinating enzymes. We are determined to identify and characterize these regulators and to use this knowledge for stabilization of IFNAR and increasing the efficacy of IFN against cancers and chronic viral infections. Conversely, we search for stimulators of IFNAR downregulation to prevent harmful effects of IFN in pathogenesis of autoimmune diseases.

Gui Jun, Katlinski Kanstantsin V, Koumenis Constantinos, Diehl J Alan, Fuchs Serge Y The PKR-like endoplasmic reticulum kinase promotes the dissemination of Myc-induced leukemic cells. [PMID 30902831] Molecular cancer research : MCR : , 2019.

Ortiz Angelica, Gui Jun, Zahedi Farima, Yu Pengfei, Cho Christina, Bhattacharya Sabyasachi, Carbone Christopher J, Yu Qiujing, Katlinski Kanstantsin V, Katlinskaya Yuliya V, Handa Simran, Haas Victor, Volk Susan W, Brice Angela K, Wals Kim, Matheson Nicholas J, Antrobus Robin, Ludwig Sonja, Whiteside Theresa L, Sander Cindy, Tarhini Ahmad A, Kirkwood John M, Lehner Paul J, Guo Wei, Rui Hallgeir, Minn Andy J, Koumenis Constantinos, Diehl J Alan, Fuchs Serge Y An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles. [PMID 30645975] Cancer cell 35: 33-45.e6, 2019.

Kumar Sushil, Srivastav Ratnesh Kumar, Wilkes David W, Ross Taylor, Kim Sabrina, Kowalski Jules, Chatla Srinivas, Zhang Qing, Nayak Anupma, Guha Manti, Fuchs Serge Y, Thomas Christoforos, Chakrabarti Rumela Estrogen-dependent DLL1-mediated Notch signaling promotes luminal breast cancer. [PMID 30442981] Oncogene 38: 2092-2107, 2019.

Ghosh Jyotirmoy, Chowdhury Anindya Roy, Srinivasan Satish, Chattopadhyay Mrittika, Bose Moumita, Bhattacharya Sabyasachi, Raza Haider, Fuchs Serge Y, Rustgi Anil K, Gonzalez Frank J, Avadhani Narayan G Cigarette Smoke Toxins-Induced Mitochondrial Dysfunction and Pancreatitis Involves Aryl Hydrocarbon Receptor Mediated Cyp1 Gene Expression: Protective Effects of Resveratrol. [PMID 30165701] Toxicological sciences : an official journal of the Society of Toxicology 166: 428-440, 2018.

Bu Yiwen, Yoshida Akihiro, Chitnis Nilesh, Altman Brian J, Tameire Feven, Oran Amanda, Gennaro Victoria, Armeson Kent E, McMahon Steven B, Wertheim Gerald B, Dang Chi V, Ruggero Davide, Koumenis Constantinos, Fuchs Serge Y, Diehl J Alan A PERK-miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival. [PMID 29230015] Nature cell biology 20: 104-115, 2018.

Zhao Bin, Bhattacharya Sabyasachi, Yu Qiujing, Fuchs Serge Y Expression of the IFNAR1 chain of type 1 interferon receptor in benign cells protects against progression of acute leukemia. [PMID 28503979] Leukemia & lymphoma 59: 171-177, 2018.

Katlinski Kanstantsin V, Gui Jun, Katlinskaya Yuliya V, Ortiz Angelíca, Chakraborty Riddhita, Bhattacharya Sabyasachi, Carbone Christopher J, Beiting Daniel P, Girondo Melanie A, Peck Amy R, Puré Ellen, Chatterji Priya, Rustgi Anil K, Diehl J Alan, Koumenis Constantinos, Rui Hallgeir, Fuchs Serge Y Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment. [PMID 28678581] Cancer cell 31: 194-207, 2017.

Gui Jun, Zhao Bin, Lyu Kaosheng, Tong Wei, Fuchs Serge Y Downregulation of the IFNAR1 chain of type 1 interferon receptor contributes to the maintenance of the haematopoietic stem cells. [PMID 28678581] Cancer biology & therapy 18: 534-543, 2017.

Ortiz Angélica, Fuchs Serge Y Anti-metastatic functions of type 1 interferons: Foundation for the adjuvant therapy of cancer. [PMID 26822709] Cytokine 89: 4-11, 2017.

Zhang Kang-Jian, Yin Xiao-Fei, Yang Yuan-Qin, Li Hui-Ling, Xu Yan-Ni, Chen Lie-Yang, Liu Xi-Jun, Yuan Su-Jing, Fang Xian-Long, Xiao Jing, Wu Shuai, Xu Hai-Neng, Chu Liang, Katlinski Kanstantsin V, Katlinskaya Yuliya V, Guo Rong-Bing, Wei Guang-Wen, Wang Da-Cheng, Liu Xin-Yuan, Fuchs Serge Y A Potent Antitumor Efficacy of Novel Recombinant Type I Interferon. [PMID 27683179] Clinical cancer research : an official journal of the American Association for Cancer Research 23: 2038-2049, 2017.

Gui Jun, Gober Michael, Yang Xiaoping, Katlinski Kanstantsin V, Marshall Christine M, Sharma Meena, Werth Victoria P, Baker Darren P, Rui Hallgeir, Seykora John T, Fuchs Serge Y Therapeutic Elimination of the Type 1 Interferon Receptor for Treating Psoriatic Skin Inflammation. [PMID 27369778] The Journal of investigative dermatology 136: 1990-2002, 2016.

Xu Zhenhua, Bu Yiwen, Chitnis Nilesh, Koumenis Costas, Fuchs Serge Y, Diehl J Alan miR-216b regulation of c-Jun mediates GADD153/CHOP-dependent apoptosis. [PMID 27173017] Nature communications 7: 11422, 2016.

Katlinskaya Yuliya V, Katlinski Kanstantsin V, Yu Qiujing, Ortiz Angelica, Beiting Daniel P, Brice Angela, Davar Diwakar, Sanders Cindy, Kirkwood John M, Rui Hallgeir, Xu Xiaowei, Koumenis Constantinos, Diehl J Alan, Fuchs Serge Y Suppression of Type I Interferon Signaling Overcomes Oncogene-Induced Senescence and Mediates Melanoma Development and Progression. [PMID 27052162] Cell reports 15: 171-180, 2016.

Davar Diwakar, Fuchs Serge Y, Kirkwood John M BRAF Inhibitors and IFNa: Plus, Minus, or Indeterminate? [PMID 26851801] Journal of the National Cancer Institute 108: , 2016.

Katlinskaya Yuliya V, Katlinski Kanstantsin V, Lasri Audrey, Li Ning, Beiting Daniel P, Durham Amy C, Yang Ting, Pikarsky Eli, Lengner Christopher J, Johnson F Brad, Ben-Neriah Yinon, Fuchs Serge Y Type I Interferons Control Proliferation and Function of the Intestinal Epithelium. [PMID 26811327] Molecular and cellular biology 36: 1124-35, 2016.

Pytel Dariusz, Gao Yan, Mackiewicz Katarzyna, Katlinskaya Yuliya V, Staschke Kirk A, Paredes Maria C G, Yoshida Akihiro, Qie Shuo, Zhang Gao, Chajewski Olga S, Wu Lawrence, Majsterek Ireneusz, Herlyn Meenhard, Fuchs Serge Y, Diehl J Alan PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor-Suppressive Versus Tumor Promoting Properties of PERK in Melanoma.[PMID 27977682] PLoS genetics 12: e1006518, 2016.

Xia Chuan, Vijayan Madhuvanthi, Pritzl Curtis J, Fuchs Serge Y, McDermott Adrian B, Hahm Bumsuk Hemagglutinin of Influenza A Virus Antagonizes Type I Interferon (IFN) Responses by Inducing Degradation of Type I IFN Receptor 1. [PMID 26676772] Journal of virology 90: 2403-17, 2015.

Yu Qiujing, Zhao Bin, Gui Jun, Katlinski Kanstantsin V, Brice Angela, Gao Yan, Li ChangHong, Kushner Jake A, Koumenis Constantinos, Diehl J Alan, Fuchs Serge Y Type I interferons mediate pancreatic toxicities of PERK inhibition. [PMID 26627716] Proceedings of the National Academy of Sciences of the United States of America 112: 15420-5, 2015.

Katlinskaya Yuliya V, Carbone Christopher J, Yu Qiujing, Fuchs Serge Y Type 1 interferons contribute to the clearance of senescent cell. [PMID 26046815] Cancer biology & therapy 16: 1214-9, 2015.

Dey Souvik, Sayers Carly M, Verginadis Ioannis I, Lehman Stacey L, Cheng Yi, Cerniglia George J, Tuttle Stephen W, Feldman Michael D, Zhang Paul J L, Fuchs Serge Y, Diehl J Alan, Koumenis Constantinos ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. [PMID 26011642] The Journal of clinical investigation 125: 2592-608, 2015.

Yu Qiujing, Katlinskaya Yuliya V, Carbone Christopher J, Zhao Bin, Katlinski Kanstantsin V, Zheng Hui, Guha Manti, Li Ning, Chen Qijun, Yang Ting, Lengner Christopher J, Greenberg Roger A, Johnson F Brad, Fuchs Serge Y DNA-damage-induced type I interferon promotes senescence and inhibits stem cell function. [PMID 25921537] Cell reports 11: 785-797, 2015.

Yu Qiujing, Carbone Christopher J, Katlinskaya Yuliya V, Zheng Hui, Zheng Ke, Luo Mengcheng, Wang P Jeremy, Greenberg Roger A, Fuchs Serge Y Type I interferon controls propagation of long interspersed element-1. [PMID 25716322] The Journal of biological chemistry 290: 10191-9, 2015.

Thom Christopher S, Traxler Elizabeth A, Khandros Eugene, Nickas Jenna M, Zhou Olivia Y, Lazarus Jacob E, Silva Ana P G, Prabhu Dolly, Yao Yu, Aribeana Chiaka, Fuchs Serge Y, Mackay Joel P, Holzbaur Erika L F, Weiss Mitchell J Trim58 degrades Dynein and regulates terminal erythropoiesis. [PMID 25241935] Developmental cell 30: 688-700, 2014.

Bhattacharya S, HuangFu WC, Dong G, Qian J, Baker DP, Karar J, Koumenis C, Diehl JA, and Fuchs SY Anti-tumorigenic effects of Type 1 interferon are subdued by integrated stress responses [PMID 23045272] Oncogene 32: 4214-21, 2013.

Chandra PK, Bao L, Song K, Aboulnasr FM, Baker DP, Shores N, Wimley WC, Liu S, Hagedorn CH, Fuchs SY, Wu T, Balart LA and Dash S HCV infection selectively impairs Type I but not the Type III IFN signaling [PMID 24215913] Am J Pathol 184: 214-229, 2014.

Sato T, Tran TH, Peck AR, Girondo MA, Liu C, Goodman CR, Neilson LM, Freydin B, Chervoneva I, Hyslop T, Kovatich AJ, Hooke JA, Shriver CD, Fuchs SY, and Rui H Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression. [PMID 23708665] Oncogene 33 : 2215-24, 2014.

Bhattacharya S, Katlinski KV, Reichert M, Takano S, Brice A, Zhao B, Yu Q, Zheng H, Carbone CJ, Katlinskaya YV, Leu NA, McCorkell KA, Srinivasan S, Girondo M, Rui H, May MJ, Avadhani NG, Rustgi AK, and Fuchs SY Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury [PMID 24480543] Embo Mol Med 6: 384-97 , 2014.

Carbone CJ and Fuchs SY Eliminative signaling by Janus kinases: role in the down-regulation of associated receptors [PMID 23959845] J Cell Biochem 115: 8-16, 2014.

Zheng H, Gupta V, Patterson-Fortin JP, Bhattacharya S, Katlinski K, Wu J, Varghese B, Carbone CJ, Aressy B, Fuchs SY, and Greenberg RA A novel BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses [PMID 24075985] Cell Rep 5: 180-193, 2013.

Xu J, Sun D, Jiang J, Deng L, Zhang Y, Yu H, Bahl D, Langenheim JF, Chen WY, Fuchs SY, and Frank SJ The role of prolactin receptor in growth hormone signaling in breast cancer cells [PMID 23192981] Mol Endocrinol 27: 266-79, 2013.

Fuchs SY Hope and Fear for Interferon: The Receptor-centric Outlook on the Future of Interferon Therapy [PMID 23570388] J Interferon Cytokine Res 33: 211-225, 2013.

Huangfu W-C, Qian J, Liu C, Liu J, Lokshin A E, Baker D P, Rui H, Fuchs S Y Inflammatory signaling compromises cell responses to interferon alpha. [PMID 21666722] Oncogene 31: 161-72, 2012.

Fuchs SY Ubiquitination-mediated regulation of interferon responses. [PMID 22394219] Growth Factors 30: 141-8, 2012.

Cho IR, Oh M, Koh SS, Malilas W, Srisuttee R, Jhun BH, Pellegrini S, Fuchs SY, and Chung YH Hepatitis B virus X protein inhibits extracellular IFN-a-mediated signal transduction by downregulation of type I IFN receptor. [PMID 22218495] Int J Mol Med 29: 581-86, 2012.

Chitnis N, Bobrovnikova-Marjon E, Pant D, Pytel D, Zheng H, Maas N, Frederick B, Kushner JA, Chodosh L, Koumenis C, Fuchs SY and Diehl JA miR-211 is a pro-survival micro-RNA that regulates chop expression in a PERK-dependent manner. [PMID 23022383] Mol Cell 48 : 353-64, 2012.

Hart LS, Cunningham JT, Datta T, Dey S, Tameire F, Lehman SL, Qiu B, Zhang H, Cerniglia G, Bi M, Li Y, Gao Y, Liu H, Li C, Maity A, Thomas-Tikhonenko A, Perl AE, Koong A, Fuchs SY, Diehl JA, Mills IG, Ruggero D, and Koumenis C Endoplasmic reticulum stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. [PMID 23143306] J Clin Invest 122: 4621-34, 2012.

Carbone CJ, Zheng H, Bhattacharya S, Lewis JR, Reiter AM, Henthorn PS, Zhang ZY, Baker DP, Ukkiramapandian R, Bence KK, and Fuchs SY Protein tyrosine phosphatase 1B is a key regulator of IFNAR1 endocytosis and a target for anti-viral therapies. [PMID 23129613] Proc Natl Acad Sci USA 109: 19226-31, 2012.

Zheng Hui, Qian Juan, Carbone Christopher J, Leu N Adrian, Baker Darren P, Fuchs Serge Y Vascular endothelial growth factor-induced elimination of the type 1 interferon receptor is required for efficient angiogenesis. [PMID 21832278] Blood 118: 4003-6, 2011.

Bhattacharya Sabyasachi, Zheng Hui, Tzimas Christos, Carroll Martin, Baker Darren P, Fuchs Serge Y Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNa via accelerating the degradation of its receptor. [PMID 21821707] Blood 118: 4179-87, 2011.

Qian Juan, Zheng Hui, Huangfu Wei-Chun, Liu Jianghuai, Carbone Christopher J, Leu N Adrian, Baker Darren P, Fuchs Serge Y Pathogen recognition receptor signaling accelerates phosphorylation-dependent degradation of IFNAR1. [PMID 21695243] PLoS pathogens 7: e1002065, 2011.

Zheng Hui, Qian Juan, Varghese Bentley, Baker Darren P, Fuchs Serge Ligand-stimulated downregulation of the alpha interferon receptor: role of protein kinase D2. [PMID 21173164] Molecular and cellular biology 31: 710-20, 2011.

Liu Jianghuai, Carvalho Lucas P, Bhattacharya Sabyasachi, Carbone Christopher J, Kumar K G Suresh, Leu N Adrian, Yau Peter M, Donald Robert G K, Weiss Mitchell J, Baker Darren P, McLaughlin K John, Scott Phillip, Fuchs Serge Y Mammalian casein kinase 1alpha and its leishmanial ortholog regulate stability of IFNAR1 and type I interferon signaling. [PMID 19805514] Molecular and cellular biology 29: 6401-12, 2009.

Plotnikov Alexandr, Varghese Bentley, Tran Thai H, Liu Chengbao, Rui Hallgeir, Fuchs Serge Y Impaired turnover of prolactin receptor contributes to transformation of human breast cells. [PMID 19276348] Cancer research 69: 3165-72, 2009.

Liu Jianghuai, HuangFu Wei-Chun, Kumar K G Suresh, Qian Juan, Casey James P, Hamanaka Robert B, Grigoriadou Christina, Aldabe Rafael, Diehl J Alan, Fuchs Serge Y Virus-induced unfolded protein response attenuates antiviral defenses via phosphorylation-dependent degradation of the type I interferon receptor. [PMID 19154989] Cell host & microbe 5: 72-83, 2009.

Ph.D. (Experimental Oncology) All-Union Cancer Research Center, Russia , 1992

M.D. Yaroslavl State Medical Institute, Russia, 1987