THE PAGANO LABORATORY
ONCOLOGY R E S E A R C H

Due to its major role many cellular pathways, the UPS has been extensively reported to be deregulated in several pathologies.  We aim at elucidating the molecular events that trigger improper functioning of the UPS in the context of oncogenesis, and how these events may be targeted in the development of a novel therapeutic strategy.  Importantly, we found a direct functional role for the SCF in the context of tumorigenesis and metastatics progression.  Previously, we found that FBXO11 targets the BCL6 oncoprotein for degradation.  BCL6 overexpression is the primary driver of oncogenesis in diffuse large B cell lymphoma (DLBCL), and FBXO11 is mutated in 20 percent of DLBCLs, resulting in BCL6 overexpression in these tumors.  Separately, we found a tissue-specific role for FBXW7 in cell survival, by targeting p100/NF-κB2, an inhibitor of NF-κB signaling, for degradation.  In multiple myeloma cells, which are addicted to constitutive NF-κB signaling, the disruption of FBXW7-dependent p100 degradation by the inhibition of GSK3β results in cell death.  Lastly, we found that the tumor suppressor PTEN competes with FBXL2 for IP3R3 binding, and the FBXL2-dependent degradation of IP3R3 is accelerated in Pten-/- mouse embryonic fibroblasts and PTEN-null cancer cells.  We then showed that inhibiting IP3R3 degradation with a small molecule in PTEN-deregulated cancers represents a valid therapeutic strategy.  Currently, we are investigating how the SCF plays a role in mediating cell migration, extravasation, and invasion of other tissues during metastatic progression in pancreatic and prostate adenocarcinomas.  We are also focusing on the ubiquitin ligase CRL3-Keap1 and its role in inducing metastasis in lung cancers.

 

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