A detailed understanding of the molecular 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.
|Dankert, John F; Rona, Gergely; Clijsters, Linda et al. (2016) Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2. Mol Cell 64:507-519|
|Duan, Shanshan; Pagano, Michele (2015) SPOP Mutations or ERG Rearrangements Result in Enhanced Levels of ERG to Promote Cell Invasion in Prostate Cancer. Mol Cell 59:883-4|
|Skaar, Jeffrey R; Ferris, Andrea L; Wu, Xiaolin et al. (2015) The Integrator complex controls the termination of transcription at diverse classes of gene targets. Cell Res 25:288-305|
|Pagan, Julia K; Marzio, Antonio; Jones, Mathew J K et al. (2015) Degradation of Cep68 and PCNT cleavage mediate Cep215 removal from the PCM to allow centriole separation, disengagement and licensing. Nat Cell Biol 17:31-43|
|Young, Lauren M; Marzio, Antonio; Perez-Duran, Pablo et al. (2015) TIMELESS Forms a Complex with PARP1 Distinct from Its Complex with TIPIN and Plays a Role in the DNA Damage Response. Cell Rep 13:451-9|
|Chen, X; Sahasrabuddhe, A A; Szankasi, P et al. (2014) Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival. Cell Death Differ 21:1535-45|
|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|
|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|
|Skaar, Jeffrey R; Pagan, Julia K; Pagano, Michele (2014) SCF ubiquitin ligase-targeted therapies. Nat Rev Drug Discov 13:889-903|
|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|
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