Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

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

11.02.2004


Finding mice suggests that abnormalities of this beta-catenin protein underlie certain muscle diseases in human



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 â-catenin, according to scientists at St. Jude Children’s Research Hospital. â-catenin is one of the key proteins that orchestrates this process. Ozz directs destruction of â-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 â-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 â-catenin at a specific cellular site, the sarcolemma — the membrane covering each muscle fiber — is achieved by the activity of the Ozz-E3 ligase. "Modulating â-catenin levels at the sarcolemma is critical for the organization of sarcomeres, the basic building units of muscle fibers, and, in turn, for the remodeling and the regeneration of skeletal and cardiac muscle," d’Azzo said.

Sarcomeres are composed in large part of two different proteins, actin and myosin. The interaction of actin and myosin pulls the ends of the sarcomere toward each other in a miniature contraction. Thousands of sarcomeres lined up in a row make a myofibril; and large bundles of myofibrils make up a muscle fiber. Muscle fibers work together to form a single muscle, whose ability to contract is based on the accumulated contractions of the many thousands of sarcomeres making up each myofibril.

"For a muscle fiber to grow, there must be a constant rearrangement of myofibrils," d’Azzo said, "and that requires the dynamic removal and replacement of membrane-bound proteins, like â-catenin, that connect the myofibrils to the sarcolemma."

The St. Jude findings indicate that the loss of Ozz function disrupts the correct assembly of sarcomeres, which in turn disrupts muscle formation. Thus, the discovery of the Ozz function during muscle remodeling and growth might help uncover the genetic cause of certain muscle diseases that occur for unknown reason and that affect children in their growing years.

This work was supported in part by NIH, a Cancer Center support grant, Phillip and Elizabeth Gross and ALSAC. d’Azzo holds an endowed chair in Genetics and Gene Therapy from the Jewelers Charity Fund; and A. John Harris was supported by grants from the New Zealand Lottery Board and Foundation for Research Science and Technology.

Other authors of the paper include Tommaso Nastasi, Antonella Bongiovanni, Yvan Campos, Linda Mann, James N. Toy, Jake Bostrom, Robbert Rottier and Christopher Hahn (St. Jude); and Joan Weliky Conaway (Stowers Institute for Medical Research, Kansas City, MO).


St. Jude Children’s Research Hospital

St. Jude Children’s Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, TN, St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit www.stjude.org.

Bonnie Cameron | EurekAlert!
Further information:
http://www.stjude.org

More articles from Health and Medicine:

nachricht Organ-on-a-chip mimics heart's biomechanical properties
23.02.2017 | Vanderbilt University

nachricht Researchers identify cause of hereditary skeletal muscle disorder
22.02.2017 | Klinikum der Universität München

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

From rocks in Colorado, evidence of a 'chaotic solar system'

23.02.2017 | Physics and Astronomy

'Quartz' crystals at the Earth's core power its magnetic field

23.02.2017 | Earth Sciences

Antimicrobial substances identified in Komodo dragon blood

23.02.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>