A detailed understanding of the nnolecular and cellular events influencing the three key dimensions of cellular life (growth/proliferation, survival, and differentiation) remains a central question in cancer biology. Further understanding of the influence of the ubiquitin system on the transformation process will help to identify novel targets for cancer therapy. The first years of work under CA76584 (started in 1998) set the bases for elucidating the role played by F-box proteins in human oncogenesis, which was accomplished during the second funding cycle. In its third cycle, CA76584 is currently devoted to elucidating the integration of the ubiquitin system in the signaling networks of the cell, and its corruption in cancer. In particular, our research program involves the study of the human family of SCF and SCF-like ubiquitin ligases to gain an understanding of the molecular mechanisms through which they control basic cellular processes, such as cell growth, cell division, and cell survival. To this end, we are using a comprehensive and interdisciplinary approach that includes biochemical and biological methods, as well as somatic cell and mouse genetics. These tools, together with our expertise in the ubiquitin system, will ensure that our laboratory will continue to contribute to the understanding of cell functions during the coming years. As the mechanisms of the ubiquitin-mediated proteolysis of cell cycle regulators are unraveled, this team is committed to the integration of its basic research results with an understanding of malignant transformation.
The knowledge gained from our studies is crucial to understanding the molecular mechanisms of malignant transformation and will facilitate translational research aimed at developing strategies for therapeutic intervention. Indeed, therapeutics that non-specifically target the pathways studied by my laboratory (e.g., proteasome inhibitors) are already a reality, and we hope that our studies will lead to more potent, specific therapeutics.
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|Kanarek, Naama; Grivennikov, Sergei I; Leshets, Michael et al. (2014) Critical role for IL-1? in DNA damage-induced mucositis. Proc Natl Acad Sci U S A 111:E702-11|
|Choi, Byeong Hyeok; Pagano, Michele; Dai, Wei (2014) Plk1 protein phosphorylates phosphatase and tensin homolog (PTEN) and regulates its mitotic activity during the cell cycle. J Biol Chem 289:14066-74|
|Horn, Moritz; Geisen, Christoph; Cermak, Lukas et al. (2014) DRE-1/FBXO11-dependent degradation of BLMP-1/BLIMP-1 governs C. elegans developmental timing and maturation. Dev Cell 28:697-710|
|Bassermann, Florian; Eichner, Ruth; Pagano, Michele (2014) The ubiquitin proteasome system - implications for cell cycle control and the targeted treatment of cancer. Biochim Biophys Acta 1843:150-62|
|Choi, Byeong Hyeok; Pagano, Michele; Huang, Chaunshu et al. (2014) Cdh1, a substrate-recruiting component of anaphase-promoting complex/cyclosome (APC/C) ubiquitin E3 ligase, specifically interacts with phosphatase and tensin homolog (PTEN) and promotes its removal from chromatin. J Biol Chem 289:17951-9|
|Jeong, Yeon-Tae; Rossi, Mario; Cermak, Lukas et al. (2013) FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress. J Cell Biol 200:141-9|
|Kuchay, Shafi; Duan, Shanshan; Schenkein, Emily et al. (2013) FBXL2- and PTPL1-mediated degradation of p110-free p85? regulatory subunit controls the PI(3)K signalling cascade. Nat Cell Biol 15:472-80|
|Jeong, Yeon-Tae; Cermak, Lukas; Guijarro, Maria V et al. (2013) FBH1 protects melanocytes from transformation and is deregulated in melanomas. Cell Cycle 12:1128-32|
|Rossi, Mario; Duan, Shanshan; Jeong, Yeon-Tae et al. (2013) Regulation of the CRL4(Cdt2) ubiquitin ligase and cell-cycle exit by the SCF(Fbxo11) ubiquitin ligase. Mol Cell 49:1159-66|
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