The Cross-Border Biotech Blog

Biotechnology, Health and Business in Canada, the United States and Worldwide

Friday Science Review: June 24, 2011

New Drug Targets in the Ubiquitin-Proteasome System?

Mount Sinai Hospital ♦ University of Montreal ♦ Structural Genomics Consortium ♦ Celgene Signal Research Division ♦ Wellcome Trust Centre for Cell Biology ♦ University of Toronto

Published in Cell, June 24, 2011

Proteins within the ubiquitin-proteasome system are responsible for modulating the stability and cellular localizations of a plethora of proteins in the human body. Usually it is the E2 enzymes that pass ubiquitin along to a variety of substrates to alter their stability. Researchers have discovered a small molecule, being coined C60651, that latches into a cryptic sight on the E2 enzyme hCdc34, changing it structural conformation and ability to transfer molecules of ubiquitin to receptor lysine residues on target substrates. Further investigation with C60651 showed that it could stunt the growth of human cancer cell lines. Presumably, the small molecule broadly affects protein stability and interferes with essential cellular processes. Thus, it could be worth investigating the deactivation of E2 enzymes as a therapeutic paradigm for cancer.

JAK2 at the Heart of Chuvash Polycythemia

University of Toronto ♦ University of North Carolina ♦ University of Pennsylvania ♦ UC San Diego ♦ Hospital for Sick Children

Published in Nature Medicine, June 19, 2011

Chuvash Polycythemia is a rare congenital disorder characterized by an increase in the total number of red blood cells. It results primarily from genetics defects in erythroid progenitors that make them either hypersensitive or insensitive to stimulation by erythropoietin. This recent study illustrates that regulation of JAK2 could be at the centre of the disease. Typically, homozygous mutations in the R200W and/or H191D genes located in the von Hippel-Lindau (VHL) gene cause the disease. Researchers show that under normal circumstances the VHL gene product binds to suppressor of cytokine signaling 1 (SOCS1) to form a dimeric ligase that marks JAK2 for ubiquitin-mediated degradation. However, after analyzing the VHL gene product in Chuvash Polycythemia, it was found that the mutant version fails to form a complex with SOCS1 and hence fails to elicit the destruction of JAK2. To substantiate their findings, investigators treated knock-in mice homozygous for the R200W mutation with a JAK2 inhibitor and showed that the disease phenotype could be reversed.

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