PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

New technique reveals cross-talk between 2 essential cellular processes

The research provides insights into programmed cell death and opens door to new approaches to cancer treatment

2012-07-20
(Press-News.org) LA JOLLA, CA – Scientists at The Scripps Research Institute have simultaneously mapped two of the most important types of protein-modification in cells, revealing their extensive cooperation during an essential cellular process.

Phosphorylation, the attachment of a phosphate group to a protein, and proteolysis, the cleavage of a protein, had almost always been studied independently. The new research combines techniques for mapping these events across all proteins in a cell population to show how they work together to execute the cellular "auto-destruct program" known as apoptosis.

The specific findings on apoptosis may lead to the development of new cancer diagnostics and drugs, since cancer treatments often aim to induce apoptosis in malignant cells. Even more importantly, the study marks the development of a basic new tool of "proteomics"—the large-scale study of proteins—that should provide useful insights into many cellular processes.

"Detecting the cross-talk between protein regulation pathways has long been a challenge, and so with this new technique we can start to do analyses that were difficult or impossible before," said Benjamin F. Cravatt, professor and chair of the Department of Chemical Physiology at Scripps Research, and member of Scripps Research's Skaggs Institute for Chemical Biology. Cravatt was the senior investigator for the study, published in the July 20, 2012 edition of the journal Cell.

Need for a Global Approach

Phosphorylation and proteolysis are among the most important mechanisms of protein modification in cells. They are mediated by enzymes, and occur after a protein has been translated from genetic material and folded. Some proteolysis and phosphorylation events serve to activate a protein so that it can take part in a purposeful cellular process; others have the effect of deactivating a protein.

Previous studies of phosphorylation and proteolysis had suggested that the two mechanisms sometimes work in tandem, especially during apoptosis. But those studies had been focused on individual apoptosis-driving enzymes and their biochemical partners, rather than on the "global" apoptosis process within cells.

"In this study, we wanted to develop a global method to let us see all the signs of cross-talk between proteolysis and phosphorylation during apoptosis," said Melissa M. Dix, a research associate in the Cravatt laboratory. Dix was a lead author of the paper, along with then-graduate student Gabriel M. Simon, who is now a postdoctoral researcher at Washington University, St. Louis.

New Insights

Dix and Simon built on an earlier proteolysis-mapping method that they had described in Cell in 2008. Known as PROTOMAP, it can be used to generate a detailed picture of the protein cleavage events in cells during a process of interest. For the new study, the researchers added a technique for detecting phosphorylation events, plus another recently-developed proteomics technology, SILAC, which enables researchers to distinguish, within a given sample, copies of proteins that have come from different cell populations. The researchers then applied the combined techniques to populations of control cells and apoptotic cells, in order to find the proteolysis and phosphorylation events that happened only during apoptosis.

They detected more than 700 apoptosis-specific proteolysis events—mostly mediated by apoptosis-driving enzymes known as caspases—including many that had not been reported before. The new mapping also revealed for the first time an extensive, apoptosis-specific network of phosphorylation events, many of which were clearly connected to proteolysis events. "Just looking at the map of phosphorylation events, we could see that they were unusually common around sites of known caspase cleavage," said Dix.

Previous studies had hinted that the phosphorylation of a protein near one of its caspase cleavage sites would always tend to block that cleavage. The new evidence suggested otherwise. "We could see that these apoptosis-specific phosphorylations sometimes persisted on caspase-cleaved fragments," said Dix.

Dix and Simon showed that these phosphorylations in some cases had enabled the caspase cleavage events; in others, cleavage events had enabled the phosphorylations. Similarly, they confirmed that some of the kinase enzymes that phosphorylate proteins during apoptosis can't do their jobs until they are cleavage-activated by caspases. "We've tended to study proteolysis and phosphorylation separately, but it's clear that they're intimately associated and need to be looked at as such," Dix said.

Potential Applications in Cancer Treatment

The Cravatt laboratory is now applying the techniques developed in this study to other analyses, starting with studies of apoptosis in a variety of cell types. The cells they used in the just-published study, Jurkat T-cells, are often used to investigate apoptosis because they can be easily induced to undergo the process. "But each cell type has its own set of working proteins, which will give it a distinct signature when it undergoes apoptosis," Cravatt said.

Techniques to detect apoptosis in specific cell types would be useful in cancer diagnostics and therapy. Tumor cells typically have evolved resistance to apoptosis, whereas chemotherapies often kill tumor cells by overcoming that resistance. Dix, Cravatt, and their colleagues are now trying to determine whether certain phosphorylated protein fragments can be used as highly specific "biomarkers" of apoptosis in cancer cells, detectable in a simple blood test. "Such a test would tell you whether or not your cancer drug is working," Cravatt said.

The wealth of data from these apoptosis studies may also help researchers devise new apoptosis-inducing cancer drugs, he notes—and apoptosis is merely one cellular process that the new mapping technique can be used to illuminate.



INFORMATION:

Other co-authors of the paper, "Functional interplay between caspase cleavage and phosphorylation sculpts the apoptotic proteome," were Cravatt laboratory members Chu Wang and Eric Okerberg; and Matthew P. Patricelli, now of ActivX Biosciences, Inc. in San Diego.

The research was funded by the National Institutes of Health, the California Breast Cancer Foundation, ActivX Biosciences, the ARCS Foundation and the Skaggs Institute for Chemical Biology at Scripps Research.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. Over the past decades, Scripps Research has developed a lengthy track record of major contributions to science and health, including laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. The institute employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards Ph.D. degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu



ELSE PRESS RELEASES FROM THIS DATE:

Debate ends: Everyone was right

2012-07-20
KANSAS CITY, MO—Scientists at the Stowers Institute of Medical Research have developed an innovative method to count the number of fluorescent molecules in a cluster and then applied the novel approach to settle a debate rampant among cell biologists—namely, how DNA twists into a unique chromosomal structure called the centromere. Knowing this helps explain how cells navigate the hazards of division and avoid the disastrous consequences of ending up with the wrong number of chromosomes. Centromeres, which sit at the cross point of the "X" used to represent duplicated ...

The Yin and Yang of stem cell quiescence and proliferation

2012-07-20
KANSAS CITY, MO—Not all adult stem cells are created equal. Some are busy regenerating worn out or damaged tissues, while their quieter brethren serve as a strategic back-up crew that only steps in when demand shoots up. Now, researchers at the Stowers Institute for Medical Research have identified an important molecular cue that keeps quiescent mouse hematopoietic (or blood-forming) stem cells from proliferating when their services are not needed. Publishing in the July 20, 2012 issue of Cell, the team led by Stowers Investigator Linheng Li, Ph.D., report that Flamingo ...

Lack of insurance linked to advanced stage cervical cancer

2012-07-20
ATLANTA –July 19, 2012—A large national sample of women diagnosed with cervical cancer between 2000 and 2007 finds lack of insurance was second only to age as the strongest predictor of late stage at diagnosis, a gap the authors say is likely attributable to lack of screening. The American Cancer Society estimates that 12,170 women will be diagnosed with cervical cancer and 4,220 women will die from the disease in 2012. Although incidence and mortality from cervical cancer have declined dramatically since the introduction of the Pap test, one in three cervical cancer ...

Preclinical data support ongoing clinical trials testing IDO inhibitors as a treatment for cancer

2012-07-20
PHILADELPHIA — Inhibitors of indoleamine 2,3-dioxygenase (IDO) are being assessed in clinical trials as a potential treatment for recurrent or refractory solid tumors. Clear genetic rationale for these trials, together with evidence that primary and metastatic lung tumors might be particularly susceptible to the drugs, is now reported in a preclinical study published in Cancer Discovery, a journal of the American Association for Cancer Research. "Our data provide preclinical genetic validation for the ongoing clinical trials testing IDO inhibitors in cancer patients," ...

Team discovers how western corn rootworm resists crop rotation

2012-07-20
CHAMPAIGN, Ill. — A new study answers a question that has baffled researchers for more than 15 years: How does the western corn rootworm – an insect that thrives on corn but dies on soybeans – persist in fields that alternate between corn and soybeans? The answer, researchers say, has to do with enzyme production in the rootworm gut. Their findings are described in a paper in Ecology and Evolution. Crop rotation declined in the middle of the 20th century as the use of insecticides and fertilizers expanded in the U.S. Then in the 1950s and '60s, when some insecticides ...

NYU Langone Medical Center's tip sheet to the Alzheimer's Association International Conference

2012-07-20
NEW YORK, JULY 15, 2012 – Experts from the Comprehensive Center on Brain Aging at NYU Langone Medical Center will present new research at The 2012 Alzheimer's Association International Conference on Alzheimer's Disease to be held in Vancouver, British Columbia, Canada, July 14 – July 19. From basic discovery to clinical applications, NYU Langone Medical Center has been at the forefront of the diagnosis and treatment of Alzheimer's disease since the 1970s. The Comprehensive Center on Brain Aging, founded upon the strengths of the Silberstein Alzheimer's Institute, is ...

Locating muscle proteins

2012-07-20
Muscle contraction and many other movement processes are controlled by the interplay between myosin and actin filaments. Two further proteins, tropomyosin and troponin, regulate how myosin binds to actin. While theoretical models have in fact described exactly how these muscle proteins interact, this interaction has never previously been observed in detail. Stefan Raunser and Elmar Behrmann from the Max Planck Institute of Molecular Physiology in Dortmund have now managed to image the actin-myosin-tropomyosin complex with an unprecedented accuracy of 0.8 nanometres, which ...

Stanford researchers first to determine entire genetic sequence of individual human sperm

2012-07-20
STANFORD, Calif. — The entire genomes of 91 human sperm from one man have been sequenced by Stanford University researchers. The results provide a fascinating glimpse into naturally occurring genetic variation in one individual, and are the first to report the whole-genome sequence of a human gamete — the only cells that become a child and through which parents pass on physical traits. "This represents the culmination of nearly a decade of work in my lab," said Stephen Quake, PhD, the Lee Otterson Professor in the School of Engineering and professor of bioengineering ...

Scientists connect seawater chemistry with climate change and evolution

2012-07-20
TORONTO, ON – Humans get most of the blame for climate change, with little attention paid to the contribution of other natural forces. Now, scientists from the University of Toronto and the University of California Santa Cruz are shedding light on one potential cause of the cooling trend of the past 45 million years that has everything to do with the chemistry of the world's oceans. "Seawater chemistry is characterized by long phases of stability, which are interrupted by short intervals of rapid change," says Professor Ulrich Wortmann in the Department of Earth Sciences ...

Does presence of oxidants early in life help determine life span?

2012-07-20
ANN ARBOR, Mich.—Why do we age, and what makes some of us live longer than others? For decades, researchers have been trying to answer these questions by elucidating the molecular causes of aging. One of the most popular theories is that the accumulation of oxygen radicals over time might be the underlying culprit in aging. Oxygen radicals are chemically reactive molecules that can damage cellular components such as lipids, proteins and nucleic acids, resulting in "oxidative stress." The possible link between oxidative stress and aging has led to the proliferation ...

LAST 30 PRESS RELEASES:

Study shows head trauma may activate latent viruses, leading to neurodegeneration

Advancements in neural implant research enhance durability

SwRI models Pluto-Charon formation scenario that mimics Earth-Moon system

Researchers identify public policies that work to prevent suicide

Korea University College of Medicine and Yale Univeristy co-host forum on Advancing Healthcare through Data and AI Innovations

Nuclear lipid droplets: Key regulators of aging and nuclear homeostasis

Driving autonomous vehicles to a more efficient future

Severe maternal morbidity among pregnant people with opioid use disorder enrolled in Medicaid

Macronutrients in human milk exposed to antidepressant and anti-inflammatory medications

Exploring the eco-friendly future of antibiotic particles

Can you steam away prostate cancer?

The CTAO becomes a European Research Infrastructure Consortium

Introduction to science journalism guide published in Albanian

Official launch of Global Heat Health Information Network Southeast Asia Hub at NUS Medicine

Childhood smoking increases a person’s risk of developing COPD

MD Anderson and Myriad Genetics form strategic alliance to evaluate clinical utility of Myriad’s molecular residual disease assay

Method can detect harmful salts forming in nuclear waste melters

Researchers reveal how psychological stress may aggravate skin allergies

International partnership aims to provide first-class osteopathy training

Reducing irrigation for livestock feed crops is needed to save Great Salt Lake, study argues

Clean energy tax credit safeguards could save taxpayers $1 trillion

New genetic biocontrol breakthrough offers hope against disease-carrying mosquitoes and agricultural pests

Sex differences in brain structure present at birth

UCLA scientist unlocks early warning signs of adolescent psychosis through genetics

Research reveals unique features of brain cells linked to neurodevelopmental conditions

Smarter memory: next-generation RAM with reduced energy consumption

Core-membrane microstructured amine-modified mesoporous biochar templated via ZnCl2/KCl for CO2 capture

Audio-guided self-supervised learning for disentangled visual speech representations

From logs to security: How process analysis is transforming access control

Dronedarone inhibits the proliferation of esophageal squamous cell carcinoma through the CDK4/CDK6-RB1 axis in vitro and in vivo

[Press-News.org] New technique reveals cross-talk between 2 essential cellular processes
The research provides insights into programmed cell death and opens door to new approaches to cancer treatment