The Philosophy of the Pagano Laboratory: What We Study, How, and Why
Our laboratory is interested in how ubiquitin-mediated proteolysis controls the three key dimensions of cellular life: proliferation, survival, and differentiation. Specifically, we aim at dissecting the biochemical and molecular mechanisms behind fundamental cellular processes that, when deregulated, result in cancer. We use an interdisciplinary approach to test new hypotheses and biological concepts.
The remarkable processivity of the Ubiquitin-Proteasome System (UPS) enables it to very rapidly eliminate protein substrates. This is achieved by utilizing more than 600 effectors (i.e., the ubiquitin ligases) rendering the whole system an exquisite example of biochemical specificity. In this regard, the ca. 230 members of the CRL (Cullin-RING-ubiquitin Ligase) family represent an extraordinary machinery of protein destruction, which unidirectionally controls the cellular abundance of regulatory proteins both temporally and spatially. Moreover, its control over a wide array of substrates renders the CRL machinery a central node in the regulation of cellular homeostasis.
Much research in my laboratory has arisen from the paradigm of the timed regulation of the mammalian cell division cycle by the UPS that I established a number of years ago. Today we have expanded our focus to five main areas: (i) cell signaling, (ii) cell cycle regulation, (iii) the DNA damage response, (iv) oncology, and (v) drug discovery.
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