Our group objective is to identify novel pathways governing cell proliferation, which are altered in cancers, to provide insights into drug resistance and predict response to chemotherapy and ionizing radiation.
Our work focuses, in particular, on two processes relevant to cancer cell survival: (1) the role of ubiquitin–mediated proteolysis and (2) metabolism of deoxyribonucleotides (dNTPs). Further investigation into these processes will prove to be a powerful tool for the design and implementation of novel therapies.
Alteration of mechanisms monitoring cell cycle progression leads to cancer whereby cell proliferation is not integrated with checkpoint control signals. Instead cancer cells tend to proliferate in an uncontrolled fashion and become insensitive to external stimuli and checkpoint signals that ensure correct execution of the cell cycle. The ubiquitin proteasome system (UPS) lies at the heart of checkpoint mechanisms and dictates the fate of cellular proteins by tagging specific proteins with the small molecule ubiquitin. Single ubiquitin molecules are added via an enzymatic cascade, in which ubiquitin is activated by a covalent linkage to an activating enzyme (E1 ubiquitin) and transferred to a conjugating enzyme (E2 ubiquitin). The E3 ubiquitin ligases mediate the transfer to a lysine residue in the substrate from E2 ubiquitin to form polyubiquitin chains. Polyubiquitinated proteins are recognised for degradation by the proteasome (Figure 1)
Human cancers contain altered UPS components and E3 ubiquitin ligases, which highlights the relevance of these proteins in regulation of cell survival and proliferation. Furthermore, the blockage of the UPS is currently exploited for the treatment of cancer through the use of bortezomib, a general inhibitor of the proteasome. Therefore, we are investigating the role of E3 ubiquitin ligases in cancer cell proliferation. Our studies will prove useful in developing effective therapies that specifically target the mechanism of action of E3 ubiquitin ligases and improve the efficacy of current approaches targeting the UPS.
Vincenzo D’Angiolella is a junior Group Leader at the CRUK/MRC Oxford Institute for Radiation Oncology. He has a Medical Degree (MD) from the University of Naples “Federico II” and completed his PhD at the same University in the field of General Pathology. Following the completion of his studies, he worked as a postdoctoral fellow at the New York University School of Medicine in the USA in the laboratory of Dr Michele Pagano. He has been awarded fellowships from AIRC (Associazione Italiana per la Ricerca sul Cancro) and AICF (American Italian Cancer Foundation) and was a Scholar of the Leukemia & Lymphoma Society from 2008 to 2011.
D'Angiolella, V., Donato, V., Forrester, F. M., Jeong, Y. T., Pellacani, C., Kudo, Y., Saraf, A., Florens, L., Washburn, M. P. & Pagano, M. 2012. Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome integrity and DNA repair. Cell, 149, 1023-34.
D'Angiolella, V., Donato, V., Vijayakumar, S., Saraf, A., Florens, L., Washburn, M. P., Dynlacht, B. & Pagano, M. 2010. SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation. Nature, 466, 138-42.
D'Angiolella, V., Esencay, M. & Pagano, M. 2013. A cyclin without cyclin-dependent kinases: cyclin F controls genome stability through ubiquitin-mediated proteolysis. Trends Cell Biol, 23, 135-40.
Skaar, J. R., D'Angiolella, V., Pagan, J. K. & Pagano, M. 2009. SnapShot: F Box Proteins II. Cell, 137, 1358, 1358 e1.
Ella Fung, DPhil Student
Ioanna Mavrommatis, Postdoctoral Researcher
Dr Benedikt Kessler, Nuffield Department of Medicine, Oxford
Dr Patrick Pollard, Nuffield Department of Medicine, Oxford