UBIQUITIN PROTEASOME PATHWAY

FUNDED COLLABORATIONS


The transcriptional activator NF-kB has a strong anti-apoptotic activity and is constitutively activated in many malignancies. The processes involved in its up-regulation have remained elusive. The goals of the component led by Dr. Ciechanover are to identify the ubiquitin system enzymes and targeting motifs within the p105 NF-kB precursor protein that are involved in its processing and to develop small molecular weight inhibitors to these enyzymes. Another goal is to understand the ubiquitin pathway mediated mechanisms involved in the degradation of inhibitors of apoptosis.

The component led by Dr. Yarden will focus on two critical aspects of systems control: (i) feedback loops involving ubiquitination-deubiquitination cycles of oncogenic receptor tyrosine kinases and (ii) analyses of micro-RNA molecules regulating signal transduction by two oncogenic growth factor receptors, namely EGFR and HER2.

Substantial data exists to support a causal link between chronic inflammation and cancer. Yet, the molecular mechanisms underlying this association have only been partially unraveled. The laboratory of Dr.Ben-Neriah will analyze signaling pathways that are abrogated by NSAID treatment in chronic hepatitis and assess their role in hepatocarcinogenesis. It will also assess the apparent contradictory effect of NF-kB inhibition in different animal models of liver cancer.

The p53 tumor suppressor protein is a sequence-specific transcription factor, activated in response to a variety of cancer-relevant stress signals. p53 inactivation is one of the most frequent genetic alterations in human cancer. The p53 protein is subject to extensive post-translational regulation. Most notably, p53 is targeted by a number of E3 ubiquitin ligases, the most prominent role being played by Mdm2 which is overexpressed in many cancers. There is evidence that at least some oncogenic effects of Mdm2 can be exerted also in the absence of p53, and that a number of additional proteins can be targeted for Mdm2-mediated ubiquitination and degradation. Dr. Oren's group will attempt to identify new Mdm2 substrates as well as proteins that affect the Mdm2-p53 interaction. They will explore the notion that p53 may possess a tumor suppressor function not only in the cancer cells proper but also in their adjacent stroma. They will also explore the significance of Mdm2 mediated histone H2B ubiquitination, with emphasis on its role in transcriptional control and on possible links with cancer, including the possibility that interference with H2B ubiquitination may selectively affect tumor cells.

Understanding the DNA damage response (DDR) is crucial to the design of better treatment regimens, minimization of side effects, identification of new targets for drug therapy, finding new methods for radiosensitization and chemosensitization of tumor cells, and resolving the major problem of radio- and drug-resistance. The group of Dr. Shiloh will employ high-throughput experimental and computational methods to identify a host of novel poly- and monoubiquitination events in the DDR mediated by the nuclear protein kinase ATM and its downstream effectors and carry out in depth functional analysis on a number of the pathways identified.

The prevalence of hypoxia and elevated levels of the hypoxia-inducible transcription factor HIF-1 in the majority of solid tumors has generated considerable interest in targeting HIF pathways as a potential basis for cancer therapeutics. This factor also plays an important role in angiogenesis and other responses after stroke and brain and spinal cord trauma and is a focus of the APNRR. An oxygen-regulated subunit, HIF-1 is recognized by an E3 ubiquitin ligase complex, ubiquitinated and targeted to proteasomal degradation. The SEPT9_V1 protein interacts with HIF-1and stabilizes it by preventing its ubiquitination and degradation, leading to increased HIF transcriptional activity. The major aim in the component led by Dr. Mabjeesh is to better understand the role of SEPT9_V1 protein in affecting the critical regulation of HIF-1 protein by the ubiquitin proteolytic system.

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