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.