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Destructive wizardry of Ozz-E3 ligase appears key to building skeletal muscles in embryos and adults

The organization and stability of growing muscles in both embryonic and adult mice depends on the ability of a protein called Ozz to direct the timely destruction of membrane-bound β-catenin, according to scientists at St. Jude Children's Research Hospital. β-catenin is one of the key proteins that orchestrates this process. Ozz directs destruction of β-catenin by assembling an active ubiquitin ligase complex, Ozz-E3, which breaks down this pool of the protein in muscle cells.

Ozz-E3's role is to attach a chain of ubiquitin molecules to β-catenin. This process, called ubiquitination, targets protein substrates for destruction and is essential to many cellular functions during development and adult life.

The researchers also discovered that the Ozz gene overlaps another gene, which codes for an enzyme called protective protein/cathepsin A or PPCA. This enzyme is a key player in a process that breaks down certain molecules in the cellular structure called the lysosome. The Ozz gene also shares with the PPCA gene a genetic "on switch," called a promoter, which controls the expression of either gene, depending on which direction the promoter acts, says Alessandra d'Azzo, Ph.D., a member of Genetics and Tumor Cell Biology at St. Jude. d'Azzo is senior author of a report on these findings that appears in the February issue of Developmental Cell.

"Our finding of the close link between PPCA and Ozz genes might explain why some children with severe neurodegenerative disease caused by mutation of PPCA also suffer from muscle disorders. We are now studying that possibility," d'Azzo said. The St. Jude team made their discoveries using muscle tissue from both normal and genetically modified mice.

The researchers showed that the delicate balance between accumulation and removal of β-catenin at a specific cellular site, the sarcolemma the membrane covering each muscle fiber is achieved by the activity of the Ozz-E3 ligase. "
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Contact: Bonnie Cameron
bonnie.cameron@stjude.org
901-495-4815
St. Jude Children's Research Hospital
10-Feb-2004


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