Ubiquitin Signaling in Cancer Biology
Covalent linkage of ubiquitin chains to cellular proteins leads to targeted degradation by the 26S proteasome, thus promoting unidirectional alteration of a divergent array of cellular processes that include cell cycle progression, signal transduction, and tumor suppression. Central to the ubiquitination reaction are the recognition of a substrate and the recruitment of an ubiquitin-conjugating enzyme that catalyzes the transfer of ubiquitin to the target protein. This dual function is executed by a cellular activity called E3 ubiquitin protein ligase.
Work from this laboratory has helped uncovering a super-family of cullin-ROC1 RING based E3 ligases. It is now widely accepted that the RING finger is the most distinct structural feature of a growing large number of cellular E3 ligases that include BRCA1-BARD1, Mdm2, c-Cbl, von Hippel-Lindau tumor suppressor complex, and Parkinson disease gene product Parkin. Recently, we have helped identifying the Nedd8 regulatory pathway that activates the cullin-ROC1 E3 ligases and continue to investigate the underlying activation mechanism. Moreover, we have discovered a novel E3 ligase complex containing CUL7, Fbx29, Skp1 and ROC1.
Our long-range goal is to understand the precise functioning of cullin-RING E3 ligases and initiate efforts to develop therapeutic strategies against human cancers.
Image: Overall structure of the Cul1–Rbx1–Skp1–F box Skp2 quaternary complex (source: Zheng et al. (2002) Nature 416).
Work from this laboratory has helped uncovering a super-family of cullin-ROC1 RING based E3 ligases. It is now widely accepted that the RING finger is the most distinct structural feature of a growing large number of cellular E3 ligases that include BRCA1-BARD1, Mdm2, c-Cbl, von Hippel-Lindau tumor suppressor complex, and Parkinson disease gene product Parkin. Recently, we have helped identifying the Nedd8 regulatory pathway that activates the cullin-ROC1 E3 ligases and continue to investigate the underlying activation mechanism. Moreover, we have discovered a novel E3 ligase complex containing CUL7, Fbx29, Skp1 and ROC1.
Our long-range goal is to understand the precise functioning of cullin-RING E3 ligases and initiate efforts to develop therapeutic strategies against human cancers.
Image: Overall structure of the Cul1–Rbx1–Skp1–F box Skp2 quaternary complex (source: Zheng et al. (2002) Nature 416).