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Researchers
  • Prof.  Yinon Ben-Neriah
Prof Yinon Ben Neriah
 
Research Interests
 
Studying the signaling of inflammation and cancer through genetically-modified mice 
 
Studying signaling pathways in animal models
Cell growth and other processes associated with cancer are regulated by several major signaling pathways, among which are the NF-kB, Wnt and the p53 activation pathways, which are of major interests to us. We have elucidated some of the key steps in NF-kB activation, including the degradation of the NF-kB inhibitor IkB (Alkalay et al, PNAS 1995; Yaron et al, EMBO J, 1997 & Nature 1998) and identified CKIα as a key component in the β-catenin destruction machinery at the core of the Wnt signaling pathway (Amit et al, Genes & Development 2002, Elyada et al, Nature 2011). We learned that studying signaling pathways in animal models is far more rewarding than tissue culture studies, and a great deal of our lab work today is carried out in genetically engineered mouse models. We engineer many model mice by ourselves, breed them onto different mutated mice and examine the models for the purpose of identifying new disease mechanisms that explain complex human pathologies.
 
Two examples of our work is spermatogenesis and tissue invasion. Using an advanced model combining knockout and inducible knockdown (mRNA depletion) of the E3 ubiquitin ligase b-TrCP, we showed how sperm differentiation depends on adhesion control, where b-TrCP regulates the adhesion molecule E-cadherin in the testis (Kanarek et al, Genes & Development 2010). This particular hybrid mouse features an inducible, transient and incomplete systemic deficiency of an enzyme, and is therefore an example of a model simulating drug-mediated inhibition. Studying another model of an inducible gut specific knockout of the enzyme CKIα we demonstrated a tissue-level function of p53, where the tumor suppressor counteracts an adverse effect of a senescence-inflammatory response and prohibits invasion of epithelial cells into the lamina propria of the gut (Elyada et al, Nature 2011).

Inflammation and Cancer
Inflammation is a fundamental protective response which sometimes goes wrong and is then a major cofactor in the pathogenesis of many chronic human diseases. We wish to understand the role of inflammation in different physiological contexts and cancer and study different aspects of inflammation in animal models of human disease. One of the main advantages of mouse models is the opportunity to observe the consequences of heterotypic (of different kinds) cell interaction and tissue dynamics. For example, using a transgenic mouse harboring a non-degradable IkB, we showed that NF-kB is a coordinator of innate immunity in the liver, where hepatocytes recruit inflammatory cells to protect the mouse against pathogenic bacteria (Lavon et al, Nature Medicine 2000). Studying the cancer-prone Mdr2-deficient mouse, we proved that NF-kB is a tumor promoter in a mouse model of hepatitis-associated liver cancer, providing one of the first molecular cues linking inflammation to cancer (Pikarsky et al, Nature 2004), and recently identified a recurrent cancer-associated amplification, which may serve as a drug target in liver cancer. Examining other mouse models lacking the microRNA processing enzyme Dicer and a specific epithelial-derived microRNA, we demonstrated a cross-talk between epithelial cells and T cells in the mouse gut which is important for mucosal immunity, and for avoiding an inflammatory bowel disease (Biton et al, Nature Immunology 2011). 
 
Much of our work it is done in collaboration with colleagues in Israel and abroad, Eli Pikarsky, Moshe Oren, Varda Rotter, Aaron Ciechanover and Kari Alitalo. Our research is funded by the organizations listed below.  
 
cell interaction and tissue dynamics
 
 
 
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Lab Members
 
   
 lab members
 
 
Ela Elyada, Ph.D - Postdoc
The Role of CKIalpha in Gut Homeostasis and Tumorigenesis
 
Irit Snir-Alkalay, Ph.D - Lab manager
Regulation of Cell Growth and Other Processes Associated with Colorectal Cancer by CKIalpha; Molecular Mechanisms and Involvement of miRNAs
Moshe Biton - Ph.D student
Involvement of miRNAs in Gut Developmet
 
Elad Horwitz - Ph.D student
Mouse Models of Hepatocellular Carcinoma
 
Naama Kanarek - Ph.D student
The Role of beta-TrCP in Gut Homeostasis
 
Guy Brachya - Ph.D student
The Role of CKIalpha in Hematopoiesis
 
Audrey Lasry - Ph.D student
The Role of CKIalpha in Intestinal Stem Cells
 
Yael Morgenstern - MD/Ph.D student
The Role of CKIdelta and CKIepsilon in Gut Homeostasis
Ido Burstein - MD/Ph.D student
Molecular Mechanisms of CKIalpha in Colorectal Cancer
 
Avivit Uliel - MD/M.Sc student
The Role of NF-kB in Hepatocellular Carcinoma
 
Orr Yaakov - Research Assistant
 
 
 
 
 
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Selected Publications
 
Ben-Neriah Y, Karin M. Inflammation meets cancer, with NF-êB as the matchmaker. Nat Immunol. 2011 12:715-23 
 
Biton M, Levin A, Slyper M, Alkalay I, Horwitz E, Mor H, Cojocaru G, Zreik F, Bentwich Z, Poy MN, Artis D, Hornstein E, Pikarsky E, Ben-Neriah Y. Epithelial microRNAs regulate gut mucosal immunity via epithelium-T cell crosstalk. Nat Immunol. 2011, 12:239-46. 
 
Elyada E, Pribluda A, Goldstein RE, Morgenstern y, Brachya G, Cojocaru G, Snir-Alkalay I, Burstain I, Haffner-Krausz R, Jung S, Wiener Z, Alitalo K, Oren M,, Pikarsky E, Ben-Neriah Y. CKIá ablation highlights a critical role of p53 in invasiveness control. Nature, 2011, 47:409-13 
 
Kanarek N, Horwitz E, Mayan I, Leshets M, Cojocaru G, Davis M, Tsuberi BZ, Pikarsky E, Pagano M, Ben-Neriah Y. Spermatogenesis rescue in a mouse deficient for the ubiquitin ligase SCF-b-TrCP by single substrate depletion. Genes Dev.  5:470-7. 2010 
 
Lee, J. Mo, J-H., Katakura, K., Alkalay, I., Liu, Y-T., Lee, H-K., Cojocaru, G., Varki, N., Kagnoff, M., Eckmann, L., Ben-Neriah, Y.* and Raz, E.*  Maintenance of Colonic Homeostasis Via Distinctive Apical TLR9 Signaling in Intestinal Epithelial CellsNature Cell Biol12: 1327-1336, 2006. *corresponding authors 
 
Pikarsky, E., Porat, R.M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E. and Ben-Neriah, Y. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature  431, 461-466, 2004. 
 
Ben-Neriah, Y. Regulatory functions of ubiquitination in the immune system. Nat Immunol. 3:20-6, 2002 
 
Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, Ben-Neriah Y*, Alkalay I.  Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev. 16:1066-76, 2002 
 
Karin, M. and Ben-Neriah, Y.  Phosphorylation meets ubiquitination:  the control of NF-kB activity.  Ann. Rev. Immunol.18:621-663, 2000. 
 
Lavon, I., Goldberg, I., Amit, S., Landsman, L., Jung, S., Tsuberi, B.Z., Barshack, I., Kopolovic, J., Galun, E., Bujard, H. and Ben-Neriah, Y.  High susceptibility to bacterial infections, but no liver dysfunction, in mice compromised for hepatocyteNF-kB activation. Nature Med., 6: 573-577, 2000 
 
Yaron, A., Hatzubai, A., Davis, M., Lavon, I., Amit, S., Manning, A.M., Andersen, J.S., Mann, M., Mercurio, F. and Ben-Neriah, Y.  Identification of the receptor component of the IkBa-ubiquitin ligase.  Nature, 396:590-594, 1998. 
 
Yaron, A., Gonen, H., Alkalay, I., Hatzubai, A., Jung, S., Beyth, S., Mercurio, F., Manning, A.M., Ciechanover, A. and Ben-Neriah, Y.  Inhibition of NF-kB cellular function via specific targeting of IkB ubiquitination.  EMBO J., 16:6486-6494, 1997.
 
 
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Open Positions
 
Excellent students who are interested in joining our lab for M.Sc, Ph.D or postdoc studies are welcome to contact Prof. Yinon Ben-Neriah (yinonb@ekmd.huji.ac.il) or Dr. Irit Snir-Alkalay (irita@ekmd.huji.ac.il).
 
 
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