Research Department of Cell Biology and Cancer Science
The Signal Transduction Laboratory of Associate Professor Aronheim Ami, current research is
focused on identification and characterization of protein-protein interaction in stress response signaling pathways. We study a novel JNK-scaffold protein WDR62 which is found to be mutated in a genetic disorder designated microcephaly. In addition, we study two members of the bZIP super family of transcription factors, JDP2 and ATF3, and revealing their role in tumorogenesis and cardiac remodeling processes. In the lab, we are using various prokaryotic and eukaryotic expression systems in vitro as well as mice models with either gain or loss of function mutations of the genes of interest and clinically relevant mouse models for cancer and cardiac research.
The Ubiquitin System in Health and Disease Laboratory of Research Professor Ciechanover Aaron (MD, DSc, Distinguished Technion Professor, Laureate, the 2004 Nobel prize in Chemistry).
Ubiquitin- and ubiquitin-like proteins-mediated modification and degradation of intracellular proteins is involved in the regulation of numerous basic cellular processes, including cell cycle progression, transcriptional activation, growth and development, differentiation, apoptosis, membrane receptor modulation, DNA repair, and the genome and proteome maintenance of quality control. In our laboratory we are using a broad array of methods – from chemistry, biochemistry, molecular biology, cell biology and imaging, fly (in collaboration with Amir Oryan’s laboratory) and mouse (in collaboration with the laboratory of Eli Pikarsky in “Hadassah:”) genetics, and modeling of diseases in mice, to study the regulated activation and degradation of transcriptional regulators such as NF-B – the major immune system modulator, p53 – a key tumor suppressor, MyoD – the major transcriptional regulator involved in muscle differentiation, and p16 – the cell cycle regulator. Interesting in particular is the case of NF-B. The regulator is activated in a two-step mechanism. Initially, the precursor protein p105 is cleaved to generate the p50 active subunit. This is a rare case in which the target molecule is processed by the ubiquitin system in a limited manner to generate a shorter active protein and not destroyed completely. The generated p50 associates with p65 to form the active heterodimeric activator that is sequestered in the cytosol following generation of a heterotrimeric complex with the inhibitor IBα. Signal-induced phosphorylation of the inhibitor leads to its rapid, ubiquitin-mediated degradation. This allows translocation of the active p50p65 activator into the nucleus where it initiates specific transcription. We have reconstituted – both in vitro and in vivo – the activation cascade of NF-B, identified the signals that protect p105 from complete destruction, and characterized the enzymes, the ubiquitin-conjugating enzymes, E2, and ligase, E3, involved. We are currently studying their mode of regulation in a chemical, biological and clinical context, e.g., possible aberrations that occur in the process in malignancies. An exciting finding is that overexpression if the ligase involved suppresses tumors growth in a dramatic manner, and we are currently studying the underlying mechanisms involved. Another focus of study in the laboratory are novel, non-canonical modes of ubiquitination – for exampole, monoubiquitination (rather than poly-) or ubiquitination on the N-terminal residue rather than on internal lysine of the target substrate. In these proteins, the N-terminal domain serves as a novel E3 recognition motif. One important protein that is targeted via this novel pathway is the cell cycle regulator/tumor suppressor protein p16INK4a.
The Tumor Progression and Agiogenesis Laboratory of Professor Neufeld Gera. Prof. Neufeld investigates molecular mechanisms that contribute to tumor progression. He has identified receptors called neuropilins that function as receptors for the major angiogenesis promoter VEGF. Neuropilins double also as receptors for axon guidance factors of the semaphorin family. These findings lead to the identification of some semaphorins as anti-angiogenic and anti-tumorigenic factors and the laboratory is currently studying their mode of action and their potential utilization as anti-cancer drugs. In addition he also identified a member of the lysyl-oxidase gene family, Loxl2, as an enzyme that promotes fibrosis and tumor metastasis. The laboratory is currently investigating the molecular mechanisms utilized by Loxl2 to promote tumor progression. A drug targeting LOXL2 that is based upon these findings is now in clinical trials.
Genetic Networks, Tissue Homeostasis and Cancer Laboratory of Associate Professor Orian (Oryan) Amir. My laboratory focuses on understanding fundamental mechanisms and genes of cancer-related genetic networks. These networks are critical for maintenance of the differentiated identity and deregulation of such networks is associated with cancer.
We focus on:
1. “Identity network”;, genes that are required to maintain the identity of differentiated cells and serve as a “barrier to tumorigenesis.”
2. NOA-gene network; Non-Oncogene Addiction genes that a essential for cancer cells to cope with the oncogenic stress, are vital for maintaining the tumorous phenotype, but are less critical to un-transformed cells. Thus, they are have the potential to be molecular targets for molecular cancer therapy.
Our current projects include:
1. Characterizing the role of SUMO-Targeted-Ubiquitin Ligase proteins in Drosophila development and human cancer.
2. Identifying genes involved in innate immune responses to distinct pathogens.
3. Delineating the genes that regulate adult gut homeostasis at the genetic and genomic level, with a focus on genes that maintain the balance between progenitor and differentiated cells.
Towards these aims we employ advanced genetic and genomic tools to study transcriptional networks using Drosophila genetics and genomics, mammalian cells, mouse-derived intestinal organoids and patient-derived specimens.
The Cancer Research Laboratory of Associate Professor Shaked Yuval. Chemotherapy, radiation, surgery and sometimes targeted drugs are the common treatment modalities for cancer. Although treatment benefit is usually achieved, cancer may often relapse. Over the years, cancer researchers attempted to uncover possible mechanisms of cancer resistance to therapy. While the majorities have searched for the selectivity and flexibility of cancer cells to escape therapy, our laboratory has focused on changes that occurred in the tumor microenvironment which can support tumor growth. We found that almost any type of anti-cancer treatment can induce host molecular and cellular effects which, in turn, can lead to tumor outgrowth and relapse despite an initial successful therapy outcome.
Tumor relapse due to host effects is attributed to angiogenesis, tumor cell dissemination from the primary tumors and seeding at metastatic sites. Various bone marrow derived cells participate in this process, and many different factors are secreted from host cells in response to the therapy which then lead to tumor relapse and even resistance to therapy.
In my laboratory research fellows, physicians, students, and research associates focus on studying these specific host effects in response to therapy can promote tumor relapse and study the clinical implications of these effects.
The Tumor Biology Research Laboratory of Professor Vlodavsky Israel. Basic and translational features of heparanase action in cancer, inflammation and kidney dysfunction.
Applying genetically engineered mice we investigate the causal involvement of heparanase, the sole heparan sulfate degrading enzyme, in the cross talk between tumor cells and the tumor microenvironment and between the epithelial compartment and cells of the immune system in cancer, inflammation and kidney disorders. The newly resolved crystal structure of the heparanase protein is being applied for rational design of heparanase-inhibiting oligosaccharides and small molecules as well as neutralizing monoclonal antibodies directed against specific domains involved in enzymatic and non-enzymatic functions of heparanase. Our premise is that the heparanase protein provides a platform to study basic aspects in cell biology and disease progression, and that drugs designed to block heparanase functions will inhibit disease progression with minimal side effects.