Description:

The Department of Biochemistry and Molecular Genetics BMG Departmental Seminar Series Presents:

"Role of Cullin Ubiquitin Ligases in B-cell proliferation"

Luca Busino, PhD
Assistant Professor, Department of Cancer Biology, University of Pennsylvania, PA

The broad focus of our research activities concerns the role of Ubiquitin Proteasome System (UPS) in B-cell growth and proliferation. The UPS is an extraordinary cellular machinery that allows for the precise temporal and spatial regulation of a large variety of regulatory proteins. This tight control is accomplished through the specific, targeted degradation of proteins via ubiquitin-mediated proteolysis. Briefly, proteins are covalently tagged with chains of the small protein ubiquitin, which allows recruitment to the proteasome for proteolysis. The polyubiquitin chain is assembled on the substrate protein via an enzymatic cascade, in which ubiquitin is activated by a covalent linkage to an E1 ubiquitin activating enzyme and transferred to an E2 ubiquitin conjugating enzyme, before an E3 ubiquitin ligase mediates transfer to a lysine residue in the substrate or a lysine (i.e. Lys48 or Lys11) in the growing polyubiquitin chain. Notably, the ultimate regulation of the reaction is dictated by the E3, which determines substrate specificity. Accordingly, the human genome encodes two E1s, 39 E2s, and over 500 E3s.

The paradigms for the multisubunit E3s are the Cullin-Ring-Ligases (CRL) complexes, which assemble using one of the five Cullin proteins as a core scaffold. All the Cullins recruit a small RING protein Rbx1 and an E2 enzyme via the C-terminus, and the N-terminus binds the bridging factors (i.e., Skp1-F-box, BTB-protein, SOCS-protein or DCAF proteins), which determines substrate specificity. Despite the large number of CRLs, only a handful of these ligases have well-established substrates and functions.

We combine genetic and proteomic approaches to identify novel ubiquitin ligases and potential substrates that play a role in the pathogenesis of B-cell lymphomas and/or multiple myeloma.