Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

ERK's got rhythm: Protein that controls cell growth found to cycle in and out of cell nucleus

02.12.2009
Time-lapsed video of individual breast tissue cells reveals a never-before-seen event in the life of a cell: a protein that cycles between two major compartments in the cell. The results give researchers a more complete view of the internal signals that cause breast tissue cells to grow, events that go awry in cancer and are targets of drug development.

The protein ERK, which helps cells respond to growth factors, travels back and forth between the nucleus, where genes are turned on and off, and the cell proper, where proteins work together to keep the cell functioning. In the video, individual cells pulsate with green light as an engineered fluorescent ERK fills the nucleus, exits and re-enters again in cycles that take about 15 minutes.

The researchers don't know if the oscillation affects the activity of other proteins in a regulatory fashion, they report in December 1 issue of Molecular Systems Biology, but find the oscillations to be regular and robust.

"True oscillations in biology are rare," said lead author Steve Wiley, chief biologist at EMSL, located at the Department of Energy's Pacific Northwest National Laboratory. "And that the oscillations of such a major growth regulator could go undiscovered for so long is extremely surprising."

ERK As Anchor

One possible function of the oscillations could be in regulating how ERK interacts with other proteins. Regardless of its biological function, ERK oscillations between compartments represent a new behavior that proteins can exhibit within cells.

Biomedical researchers need an accurate mathematical model in hand to test anti-cancer drugs. Adding ERK oscillations into the model allowed Wiley's group to make better predictions about how breast cells will respond to changes in their environment, such as the presence of growth factors or cancer drugs.

"Current models used in drug development behave very differently from the model we came up with," said Wiley. "The oscillations anchored our model in reality."

Round and Round

The meaning of the handful of oscillations found by researchers within cells has been controversial. Calcium levels cycle up and down in nerve cells, but scientists still debate why 20 years after the discovery. The production and destruction of the well-known cancer-related protein p53 continuously cycles, but its purpose is unclear. ERK is one protein in a long chain of command involved in cell growth. Because ERK gets repeatedly activated and deactivated by various proteins, Wiley and colleagues thought it might oscillate.

ERK has a role in human breast tissue, where the molecule epidermal growth factor, or EGF, sends a message from the cell surface to the rest of the cell in a carefully regulated manner that includes ERK. In breast cancer, that chain of command goes awry and cells grow out of control. Cancer drug researchers target players in the chain of command to control that growth.

For that reason, Wiley and his colleagues wanted to better understand EGF's chain of command, also known as its signaling pathway. Most researchers use cancer cells, which are easy to manipulate in culture, but Wiley studied healthy breast tissue to find out what goes on in normal cells. In addition, most research examines the population of cells on average, in which individual differences between cells can get lost. This work watched single cells.

Green Eggs

Researchers know a lot about what activates ERK and what shuts it down in the EGF signaling pathway. To follow ERK, the scientists engineered healthy, cultured breast cells to produce a green-glowing version of the protein. When EGF turns on the signaling pathway, the team verified that the green version of ERK is activated in the same way as the regular version is, by the addition of a chemical group. Other proteins deactivate ERK by removing the chemical group, and the process repeats.

To see what happens in the cells, the team put the culture dishes under a microscope that took pictures automatically once a minute. Then they removed EGF from the cells' culture and let them settle in and quiet down. The cells looked like fried eggs awash in light green.

When the team returned EGF to the culture dishes, the nucleus within cells -- what looks like an egg yolk -- brightened up with green, indicating the ERK proteins were flooding into the nucleus. After a few minutes, the green drained from the nucleus back into the cell proper, only to return again after some time. The oscillations in individual cells cycled about every 15 minutes, starting out in sync but losing that coordination over time.

Also, the time-lapse video showed that cell reproduction didn't seem to affect the cycling. The oscillations continued regularly throughout cell growth. Then the oscillations briefly stopped while one cell divided into two daughter cells. As cell division finished up, the oscillations resumed.

Additional experiments showed the oscillations required EGF in the cell culture and continued for up to ten hours, the longest period of time the researchers observed. In addition, the number of cells with oscillating ERK depended on how crowded the living conditions were. For example, the team found that at the lowest numbers of cells, all of them showed oscillating ERK. As the cells reproduced, fewer cells oscillated. By the time the cells filled the whole surface of their dish, virtually all of the cells lost their cycling ERK.

A Model ERK

One way scientists determine how well they understand the workings of a cell is to see if they can simulate it in a computer program. Wiley and his colleagues developed such a model that included the oscillating ERK, as well as most of the players in the chain of command from EGF receptor on.

To test the model, the team first used the model to predict how the oscillations would behave under conditions that kept ERK activated for a prolonged period of time. The model predicted the oscillations would die out if ERK stayed on. When the team performed a biochemical experiment in which they prevented ERK from de-activating, the percentage of cells oscillating dropped off, as the model predicted.

To further explore the biological significance of the ERK cycles, Wiley's group would like to test whether other growth factors cause ERK to oscillate in breast cells and whether different types of cells exhibit the same sort of oscillations. Ultimately, they would like to know if they can tweak the oscillation to see how things change inside the cell.

Reference: Harish Shankaran, Danielle L. Ippolito, William B. Chrisler, Haluk Resat, Nikki Bollinger, Lee K. Opresko and H. Steven Wiley, Rapid and Sustained Nuclear-Cytoplasmic ERK Oscillations Induced by Epidermal Growth Factor, Mol Syst Biol, DOI 10.1038/msb.2009.90 (http://www.nature.com/msb/index.html).

This work was supported by PNNL as part of its systems biology initiative and the National Institutes of Health.

EMSL, the Environmental Molecular Sciences Laboratory, is a national scientific user facility sponsored by the Department of Energy's Office of Science, Biological and Environmental Research program that is located at Pacific Northwest National Laboratory. EMSL offers an open, collaborative environment for scientific discovery to researchers around the world. EMSL's technical experts and suite of custom and advanced instruments are unmatched. Its integrated computational and experimental capabilities enable researchers to realize fundamental scientific insights and create new technologies. EMSL's Facebook page.

Pacific Northwest National Laboratory is a Department of Energy Office of Science national laboratory where interdisciplinary teams advance science and technology and deliver solutions to America's most intractable problems in energy, national security and the environment. PNNL employs 4,250 staff, has a $918 million annual budget, and has been managed by Ohio-based Battelle since the lab's inception in 1965. Follow PNNL on Facebook, Linked In and Twitter.

Mary Beckman | EurekAlert!
Further information:
http://www.pnl.gov

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

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

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>