Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene that drives cells to commit suicide also plays key role in development of skeletal muscle

12.03.2003


St. Jude scientists say FKHR protein causes primitive cells called myoblasts to fuse, while deficiency of FKHR contributes to muscle cancer



Investigators at St. Jude Children’s Research Hospital have discovered that a protein causing mature cells to commit suicide also helps primitive muscle cells called myoblasts fuse together, allowing them to develop into muscles. The finding of this unexpected new role for the protein, called FKHR, suggests that future research might offer clues to how mutated forms of this molecule cause a form of muscle cancer in children called rhabdomyosarcoma.

Rhabdomyosarcoma is a highly malignant tumor arising when primitive cells called myoblasts do not fuse and differentiate into muscle, but rather grow uncontrollably. Rhabdomyosarcoma accounts for 5-8 percent of childhood cancers and is usually diagnosed within the first 10 years of life. The most aggressive form of rhabdomyosarcoma is the alveolar type, which usually affects muscles in the extremities or trunk. The other most common type, embryonal rhabdomyosarcoma, occurs in the head and neck region and genitourinary tract. The discovery of the role of FKHR is important because of the protein’s link to a childhood cancer. Mutations of the FKHR gene occur when a piece of either of two genes—PAX3 or PAX7—break away from their own chromosomes and attach to FKHR forming PAX3-FKHR or PAX7-FKHR “fusion genes.” These genes then cause rhabdomyosarcoma. Understanding the normal role of FKHR in myoblasts could help explain how the mutated FKHR genes cause cancer, according to the St. Jude researchers.


The study shows that FKHR not only has at least two different jobs, but also gets controlled in either of two different ways, depending on the context in which it works.

FKHR is a transcription factor, which regulates the activity of other specific genes, and in that way controls specific cellular processes.

“The fact that FKHR plays such vastly different roles depending on where it is, forces us to reassess the impact that a single transcription factor can have on cells,” said Gerard C. Grosveld, Ph.D., chairman of the St. Jude Department of Genetics. “It also alerts us to the possibility that a mutated transcription factor can have an unexpected role in a disease we’re already familiar with.” Grosveld is senior author of a report on these findings published in the March 3 issue of The EMBO Journal.

Using a variety of techniques in molecular biology, Grosveld and his co-author Philippe R. J. Bois, Ph.D., studied the movement of FKHR in the cell between the cytoplasm (main area of the cell) and the nucleus (compartment that holds the DNA) under varying conditions. They also studied the activation of genes by FKHR.

The St. Jude researchers found that as myoblasts multiply, most of the FKHR is found in the cytoplasm rather than the nucleus. That’s because the nucleus appears to continuously export the protein out of the nucleus and into the cytoplasm, according to Grosveld. But when a myoblast starts to differentiate, the rate at which FKHR is exported from the nucleus greatly decreases, as does the rate at which the cell breaks down this transcription factor. This causes the concentration of FKHR in the nucleus to rise. Differentiation is the process during which a primitive cell develops characteristics that make it a mature cell with a specific function.

“In the nucleus of the myoblast, FKHR binds to the DNA, where it activates genes that control the cell’s ability to fuse with other myoblasts and form muscles,” Grosveld said. “So it makes sense that raising the concentration of FKHR in the nucleus will permit this transcription factor to control the fusion process.” The St. Jude researchers found that FKHR is regulated by one process in most cells, but in a different way in myoblasts. In most cells, FKHR responds to hostile environments by stimulating a cascade of biochemical reactions that executes a process called programmed cell death, or apoptosis. But this activity is blocked when an enzyme called Akt attaches a phosphate molecule to each of three sites on FKHR. Phosphate is a molecule made up of a phosphorus atom and four oxygen atoms and is often used as a way to activate or inactivate various proteins that control signaling pathways in the cell.

However, in myoblasts undergoing differentiation, a different, unknown enzyme places phosphate molecules onto FKHR. This normally controls the activity of FKHR and the rate of myoblast fusion.

“It’s somewhat like pushing a button on a machine when it’s in different parts of the same factory, and seeing the machine respond in two different ways,” Grosveld said. “If you push the button when the machine is in one place, you stop the machine from doing a job you know it’s supposed to do. But if you push the button when the machine is in another part of the factory, it does a job you didn’t even know it could do.”

One of the most interesting observations the St. Jude researchers made is that when the level of FKHR in myoblasts is reduced, these cells no longer fuse. Grosveld and Bois propose that the reduced FKHR activity in the myoblasts contributes to their inability to fuse and helps these cells to become cancerous and cause rhabdomyosarcoma.


This work was supported in part by the National Cancer Institute, a cancer center (CORE) support grant and by ALSAC.

Philippe Bois is a fellow of the Van Vleet foundation in Memphis.

St. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital, in Memphis, Tennessee, was founded by the late entertainer Danny Thomas. The hospital is an internationally recognized biomedical research center dedicated to finding cures for catastrophic diseases of childhood. The hospital’s work is supported through funds raised by ALSAC. ALSAC covers all costs not covered by insurance for medical treatment rendered at St. Jude Children’s Research Hospital. Families without insurance are never asked to pay. For more information, please visit www.stjude.org.

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

More articles from Life Sciences:

nachricht How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH

nachricht A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Quantum thermometer or optical refrigerator?

23.06.2017 | Physics and Astronomy

A 100-year-old physics problem has been solved at EPFL

23.06.2017 | Physics and Astronomy

Equipping form with function

23.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>