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 Single-stranded DNA and RNA origami go live
15.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard

nachricht New antbird species discovered in Peru by LSU ornithologists
15.12.2017 | Louisiana State University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: First-of-its-kind chemical oscillator offers new level of molecular control

DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.

Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Engineers program tiny robots to move, think like insects

15.12.2017 | Power and Electrical Engineering

One in 5 materials chemistry papers may be wrong, study suggests

15.12.2017 | Materials Sciences

New antbird species discovered in Peru by LSU ornithologists

15.12.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>