Showing papers by "J. Wade Harper published in 2006"
TL;DR: Recent advances linking UPS components with specific human diseases, most prominently cancer and neurodegenerative disorders, are reviewed and potential sites of therapeutic intervention along the regulated protein-degradation pathway are emphasized.
Abstract: Regulated protein turnover via the ubiquitin-proteasome system (UPS) underlies a wide variety of signalling pathways, from cell-cycle control and transcription to development. Recent evidence that pharmacological inhibition of the proteasome can be efficacious in the treatment of human cancers has set the stage for attempts to selectively inhibit the activities of disease-specific components of the UPS. Here, we review recent advances linking UPS components with specific human diseases, most prominently cancer and neurodegenerative disorders, and emphasize potential sites of therapeutic intervention along the regulated protein-degradation pathway.
582 citations
TL;DR: These studies uncover diverse substrate receptors for Cul4 and identify Cdt2 as a conserved component of the Cul4-Ddb1 E3 that is essential to destroy Cdt1 and ensure proper cell cycle regulation of DNA replication.
573 citations
TL;DR: A requirement for the transcription factor myocyte enhancer factor 2A (MEF2A) in the morphogenesis of postsynaptic granule neuron dendritic claws in the cerebellar cortex is reported.
Abstract: Postsynaptic differentiation of dendrites is an essential step in synapse formation. We report here a requirement for the transcription factor myocyte enhancer factor 2A (MEF2A) in the morphogenesis of postsynaptic granule neuron dendritic claws in the cerebellar cortex. A transcriptional repressor form of MEF2A that is sumoylated at lysine-403 promoted dendritic claw differentiation. Activity-dependent calcium signaling induced a calcineurin-mediated dephosphorylation of MEF2A at serine-408 and, thereby, promoted a switch from sumoylation to acetylation at lysine-403, which led to inhibition of dendritic claw differentiation. Our findings define a mechanism underlying postsynaptic differentiation that may modulate activity-dependent synapse development and plasticity in the brain.
451 citations
TL;DR: It is demonstrated that Thr286-phosphorylated cyclin D1 is recognized by a Skp1-Cul1-F box (SCF) ubiquitin ligase where FBX4 and αB crystallin govern substrate specificity.
317 citations
TL;DR: A virtual explosion in the field of Ubiquitin binding proteins has revealed several new classes and interactions with distinct surfaces on ubiquitin, providing a clearer understanding of how sorting of ubiquitinated proteins is achieved.
127 citations
TL;DR: Results demonstrate that Fbx4 is a central regulator of Pin 2/TRF1 protein abundance and that alterations in the stability of Pin2/ TRF1 can have a dramatic impact on telomere length.
105 citations
22 citations
TL;DR: Five recent reports uncover new mechanisms controlling the recovery phase of the checkpoint response, and introduce crucial roles for Claspin, Rad17 phosphorylation and the ubiquitin proteasome pathway in Chk1 signaling.
19 citations
TL;DR: Regulated protein degradation via polyubiquitination controls almost every aspect of eukaryotic cellular biology; however, the precise mechanism by which specifically linked polyUBiquitin chains are formed on target proteins as well as how the processivity of chain elongation is achieved remains a mystery.
Abstract: Regulated protein degradation via polyubiquitination controls almost every aspect of eukaryotic cellular biology; however, the precise mechanism by which specifically linked polyubiquitin chains are formed on target proteins as well as how the processivity of chain elongation is achieved remains a mystery. Recent work using the yeast ubiquitin ligase SCF(Cdc4) and the ubiquitin conjugating enzyme, Cdc34, has helped to answer these questions by identifying the determinants of lysine-48 specific ubiquitin chain polymerization.
7 citations