How Do Cells Sense And Respond To Messages? Major Signal Transduction Discovery Made

Source:

http://www.sciencedaily.com/releases/2007/10/071004121038.htm

Science Daily — The chemical process known as acetylation plays a central role in cytokine receptor signal transduction – a fundamental biochemical cascade inside cells that controls the activity of antiviral and tumor-suppressing genes.
A team of cell biologists led by Eugene Chin, M.D., a research professor at The Warren Alpert Medical School of Brown University and a staff researcher at Rhode Island Hospital, reports its findings in the journal Cell. Their results are surprising.
Scientists have long known that phosphorylation, an amino acid modifying process in proteins, is critical for switching receptors on and off on the surface of cells. Chin and his team studied how type 1 interferon binds to a receptor complex, known as the IFN-α receptor, on the cell surface to trigger an immune response. Chin and his team found that acetylation, another chemical process that modifies amino acids, plays a central role in activating interferon receptors.
Interferons play a crucial role in the body’s defense against infection and uncontrolled cell growth. Type 1 interferon is widely used to treat hepatitis B and C and cancers such as melanoma and leukemia.
“This is a major discovery in the field of signal transduction,” Chin said. “Tyrosine phosphorylation has so far been considered the major player in signal transduction. But what we discovered challenges this concept. We found another player – acetylation – in the process.”
In their experiments, Chin and his team looked at how cells respond to type 1 interferon, a protein produced in response to a viral infection or other immune trigger. The researchers found that type 1 interferon receptors, which are found in every cell in the body, call up cytoplasmic CREB-binding protein, or CBP, to move up to the cell surface. CPB acetylates these receptors. That, in turn, sparks a biochemical cascade that attracts more proteins to create a complex called ISGF3. To activate this protein complex, Chin found, acetylation is required. Once that occurs, the complex travels to the cell nucleus to switch on anti-viral or tumor-suppressing genes.
The discovery of the acetylation of cytokine receptors marks a milestone in the study of signal transduction, the process of how cells receive and respond to chemical messages.
Many diseases, such as diabetes, cancer and heart disease, occur when signal transduction goes awry. That is why some drugs either inhibit or amplify signaling inside cells by targeting tyrosine phosphorylation. By showing that another chemical process is critical to signal transduction, Chin’s findings may explain why some anti-cancer or anti-viral drugs do not work for everyone. The findings provide an important new target for therapies that fight cancer and viral infectious diseases.
The Brown research team also included Xiaoli Tang, Jin-Song Gao, and Ying-jie Guan, all post-doctoral research associates in Chin’s Rhode Island Hospital laboratory. Bharat Ramratnam, associate professor of medicine at Brown, also assisted with the research along with Katya McLane, a scientist with Upstate/Chemicon International Inc.
The National Cancer Institute funded the work.
Note: This story has been adapted from material provided by Brown University.

Fausto Intilla
www.oloscience.com

New Telomere Discovery Could Help Explain Why Cancer Cells Never Stop Dividing

Source:

http://www.sciencedaily.com/releases/2007/10/071004143131.htm

Science Daily — A group working at the Swiss Institute for Experimental Cancer Research (ISREC) in collaboration with the University of Pavia has discovered that telomeres, the repeated DNA-protein complexes at the end of chromosomes that progressively shorten every time a cell divides, also contain RNA.

This discovery, published in Science Express, calls into question our understanding of how telomeres function, and may provide a new avenue of attack for stopping telomere renewal in cancer cells.
Inside the cell nucleus, all our genetic information is located on twisted, double stranded molecules of DNA which are packaged into chromosomes. At the end of these chromosomes are telomeres, zones of repeated chains of DNA that are often compared to the plastic tips on shoelaces because they prevent chromosomes from fraying, and thus genetic information from getting scrambled when cells divide.
The telomere is like a cellular clock, because every time a cell divides, the telomere shortens. After a cell has grown and divided a few dozen times, the telomeres turn on an alarm system that prevents further division. If this clock doesn't function right, cells either end up with damaged chromosomes or they become "immortal" and continue dividing endlessly -- either way it's bad news and leads to cancer or disease. Understanding how telomeres function, and how this function can potentially be manipulated, is thus extremely important.
The DNA in the chromosome acts like a sort of instruction manual for the cell. Genetic information is transcribed into segments of RNA that then go out into the cell and carry out a variety of tasks such as making proteins, catalyzing chemical reactions, or fulfilling structural roles. It was thought that telomeres were "silent" -- that their DNA was not transcribed into strands of RNA. The researchers have turned this theory on its head by discovering telomeric RNA and showing that this RNA is transcribed from DNA on the telomere.
Why is this important" In embryonic cells (and some stem cells), an enzyme called telomerase rebuilds the telomere so that the cells can keep dividing. Over time, this telomerase dwindles and eventually the telomere shortens and the cell becomes inactive. In cancer cells, the telomerase enzyme keeps rebuilding telomeres long past the cell's normal lifetime. The cells become "immortal", endlessly dividing, resulting in a tumor. Researchers estimate that telomere maintenance activity occurs in about 90% of human cancers. But the mechanism by which this maintenance takes place is not well understood. The researchers discovered that the RNA in the telomere is regulated by a protein in the telomerase enzyme. Their discovery may thus uncover key elements of telomere function.
"It's too early to give yet a definitive answer," to whether this could lead to new cancer therapies, notes Joachim Lingner, senior author on the paper. "But the experiments published in the paper suggest that telomeric RNA may provide a new target to attack telomere function in cancer cells to stop their growth."
Joachim Lingner is an Associate Professor at the EPFL (Ecole Polytechnique Fédérale de Lausanne). Funding for this research was provided in part by the Swiss National Science Foundation NCCR "Frontiers in Genetics".
Article: "Telomeric Repeat Containing RNA and RNA Surveillance Factors at Mammalian Chromosome Ends"
Note: This story has been adapted from material provided by Ecole Polytechnique Fédérale de Lausanne.

Fausto Intilla

www.oloscience.com

Sizing Cells Up: Researchers Pinpoint When A Cell Is Ready To Reproduce

Source:

http://www.blogger.com/post-create.g?blogID=4305283407805626298

Science Daily — For more than 100 years, scientists have tried to figure out the cell size problem: How does a cell know when it is big enough to divide?

In research conducted in budding yeast (Saccharomyces cerevisiae), scientists at Rockefeller University have now identified the cellular event that marks the moment when a cell knows it is big enough to commit to cell division and spawn genetic replicas of itself. The findings provide a precise and quantitative framework for studying the possible mechanisms that allow cells to monitor and sense their size.
During the first phase of the cell cycle, known as G1, budding yeast grows and begins to form a bud; in the final stage, the cell splits into two — one bigger than the other. Although researchers have identified several key proteins that regulate and play a role in coordinating cell growth and division during G1, they have not been able to get to the core mechanism that senses whether a cell possesses enough resources to divide. Scientists needed a way to organize and confidently sort out molecular candidates involved in cell size control from those that played other roles.
Graduate student Stefano Di Talia, a biophysicist, and postdoc Jan Skotheim, an applied mathematician, provided just that. Working with Eric Siggia, head of the Laboratory of Theoretical Condensed Matter Physics, and Fred Cross, head of the Laboratory of Yeast Molecular Genetics, Di Talia and Skotheim showed that a unique cellular event, the exiting of the protein Whi5 from the nucleus, separates G1 into two independent steps: one controlled by a sizer (T1) and one controlled by a timer (T2). T1 begins when the mother and daughter cells have completely separated from each other; T2 starts in G1 once Whi5 has exited the nucleus and lasts until the new daughter cell forms its own bud.
“You need some way to know how big you are,” says first author Di Talia, whose work appears in the August 23 issue of Nature. “This precise quantitative framework allows us to narrow down the possibility of events that are involved in size control.”
By measuring the sizes of budding yeast and how long they spend in G1 and in T1, Di Talia saw that daughter cells, which are much smaller than their mother cells, need to spend more time in T1 growing. Once daughter cells reach the required size for division, they spend as much time as their mothers in T2, subsequently replicating their DNA and producing daughter cells of their own. Di Talia and his colleagues used genetics to show that a different medley of proteins coordinate cell growth and division during T1 and T2, a crucial finding highlighting that these two parts of G1 are independent from each other and are regulated by different mechanisms.
“If we continue to identify the molecular events that change how T1 is regulated,” says Di Talia, “we can really hope to get to the core of what the size-sensing machinery is.”
Nature 448(7156): 947-951 (August 23, 2007)
Note: This story has been adapted from material provided by Rockefeller University.

Fausto Intilla

www.oloscience.com

Beyond A 'Speed Limit' On Mutations, Species Risk Extinction

Source:

http://www.sciencedaily.com/releases/2007/10/071001172753.htm

Science Daily — Harvard University scientists have identified a virtual "speed limit" on the rate of molecular evolution in organisms, and the magic number appears to be 6 mutations per genome per generation -- a level beyond which species run the strong risk of extinction as their genomes lose stability.
By modeling the stability of proteins required for an organism's survival, Eugene Shakhnovich and his colleagues have discovered this essential thermodynamic limit on a species's rate of evolution. Their discovery, published recently in the Proceedings of the National Academy of Sciences, draws a crucial connection between the physical properties of genetic material and the survival fitness of an entire organism.
"While mathematical genetics research has brought about some remarkable discoveries over the years, these approaches always failed to connect the dots between the reproductive fitness of organisms and the molecular properties of the proteins encoded by their genomes," says Shakhnovich, professor of chemistry and chemical biology in Harvard's Faculty of Arts and Sciences. "We've made an important step toward finally bridging the gap between macroscopic and microscopic biology."
According to Shakhnovich, crucial aspects of an organism's evolutionary fitness can be directly inferred by inspecting its DNA sequences and analyzing how the proteins encoded by those sequences fold. DNA sequences encode the order of amino acids in a protein, and amino acids act as the protein's basic building blocks by arranging themselves into a structure that allows the protein to perform its biological function.
The research was inspired in part by the longstanding recognition that knocking out essential genes, making them inactive, produces a lethal phenotype, or a physiologically unviable organism.
"From there, we made the simple assumption that in order for an organism to be viable, all of its essential genes -- those that support basic cell operations -- have to encode at least minimally stable proteins," says Shakhnovich. "What occurs over the long process of evolution is that random mutations can either encode slightly more or less stable proteins."
If enough mutations push an essential protein towards an unstable, non-functional structure, the organism will die. Shakhnovich's group found that for most organisms, including viruses and bacteria, an organism's rate of genome mutation must stay below 6 mutations per genome per generation to prevent the accumulation of too many potentially lethal changes in genetic material.
The existence of a mutation limit for viruses helps explain how the immune system can perform its function. Because viral replication and survival can only occur at a limited rate, the body has a window of time to develop antibodies against infectious agents. Furthermore, if the mutation rate is high, the size of the genome in question must be small to stay within the bounds of the speed limit -- thus organisms that tend to mutate quickly are those with concise genomes, such as viruses and bacteria.
The Shakhnovich speed limit also offers an explanation for observed differences in genome sizes between organisms with genome error correction -- such as bacteria, mammals, birds, and reptiles -- and those without, such as RNA viruses: In more complex organisms, cells have evolved correction systems to detect and fix errors in DNA replication. These systems drastically reduce the number of mutations per replication, increasing the mutational stability of the genome and allowing more intricate and delicate biological systems to develop without the risk of interruptive mutations.
"It's an interesting corollary because it suggests that there is a fundamental tradeoff between evolutionary security and adaptive flexibility: Larger, more complex organisms have to have error correction to protect organismic viability, but this means the rate of evolution slows down significantly," Shakhnovich says. "As organisms become more complex, they have more to lose and can't be as radically experimental with their genomes as some viruses and bacteria."
Co-authors on the paper are Konstantin B. Zeldovich of the Department of Chemistry and Chemical Biology and Peiqiu Chen of the departments of Physics and of Chemical and Chemical Biology in Harvard's Faculty of Arts and Sciences. Their work is funded by the National Institutes of Health.
Note: This story has been adapted from material provided by Harvard University.

Fausto Intilla
www.oloscience.com

Indian Bug Is The Ancestor Of Crohn's Disease Pathogen

Source:

http://www.sciencedaily.com/releases/2007/10/071002213435.htm

Science Daily — An Indian team of researchers led by Seyed E. Hasnain of the Institute of Life Sciences (ILS), University of Hyderabad, India has found that a seemingly unknown mycobacterial organism Mycobacterium indicus pranii (MIP) could be the earliest ancestor of the 'generalist' branch of mycobacterial pathogens.
The 'generalist' bacteria infect anything from cockroaches to human and are capable of surviving in soil and water as against human adapted 'specialists' such as tubercle and leprosy bacilli. TB, a disease that killed about 1.7 million humans last year alone, is caused by a member of the Mycobacterial family of pathogens.
The finding further suggests that the prominent 'generalist' pathogen M. avium which seriously haunts AIDS patients, together with its close associate M. avium paratuberculosis (MAP), the agent of Crohn's disease in humans and Johne's disease in cattle descended from the MIP. It was also found that the MIP and the MAP bacilli initially inhabited water bodies and infected marine organisms predated by fishes finally arriving on soil through bird-droppings.
The MIP bacilli, also called as Mycobacterium w (Mw) were first isolated in India by G. P. Talwar at the All India Institute of Medical Sciences, New Delhi, in eighties and it is currently used, after an extensive and perhaps the largest clinical trial in the world, as an immunotherapeutic against leprosy in India.
The success with MIP based leprosy vaccine has led to human clinical evaluations of MIP in interventions against HIV-AIDS, psoriasis and bladder cancer in India. MIP, commercially available as 'Immuvac', is currently the focus of advanced multi-centric phase III clinical trials for its antituberculosis efficacy.
The comparative genomics study based on complete sequence of the MIP organism published in PLoS One reports observations based on the first ever whole genome sequencing project from India, carried out jointly by the ILS, the Centre for DNA fingerprinting and Diagnostics also at Hyderabad and the University of Delhi.
The study provides an important evolutionary basis for the acquisition and optimization of virulence in mycobacteria and determinants of boundaries therein. Similarly these efforts constitute a step forward in understanding the role of non-pathogenic and saprophytic mycobacteria in immunomodulation and in triggering innate immune responses. The study advocates exploitation of genetic similarity between MIP and MAP as a plausible advantage for therapeutic intervention against Crohn's and Johne's diseases.
Citation: Ahmed N, Saini V, Raghuvanshi S, Khurana JP, Tyagi AK, et al (2007) Molecular Analysis of a Leprosy Immunotherapeutic Bacillus Provides Insights into Mycobacterium Evolution. PLoS ONE 2(10): e968. doi:10.1371/journal.pone.0000968
Note: This story has been adapted from material provided by Public Library of Science.

Fausto Intilla
www.oloscience.com

First-ever Atomic-detail Computer Simulation Of How Proteins May Vibrate In A Crystal Completed

Source:

http://www.sciencedaily.com/releases/2007/09/070927113146.htm

Science Daily — An international collaboration directed by an Oak Ridge National Laboratory researcher has performed the first-ever atomic-detail computer simulation of how proteins vibrate in a crystal.

Jeremy Smith, who leads ORNL's Center for Molecular Biophysics, said experimental testing of the theoretical work will require the capabilities of the Office of Science's recently completed Spallation Neutron Source at ORNL.
The study is a collaboration between Smith, who also holds a University of Tennessee-ORNL Governor's Chair, and researchers from the California Institute of Technology and the National Institute of Chemistry, Ljubljana, Slovenia.
Understanding how proteins--life's worker molecules--interact with each other is a major goal of biological sciences. The simulation, which was made possible by recent advances in scientific computing, describes the forces and vibrations involved in protein crystals, which provide an environment in which the proteins are ordered and thus lend themselves to detailed study.
According to Smith, lattice dynamics describe how the repeating units of a crystal vibrate relative to each other. The resulting "phonon dispersion relations" relate the frequencies to the wavelengths of the oscillations.
Phonon dispersion relations provide information on how proteins interact with each other that could be useful for understanding protein-protein interactions in the living cell. Until now, researchers have lacked the computing power to allow atomic-detail lattice dynamical calculations.
Smith said the PRL paper predicts the existence and forms of the protein crystal lattice modes.
"In doing so it throws out a challenge to next-generation neutron science to finally make the breakthrough and determine the forms and frequencies of the vibrations experimentally," he said.
In other words, having overcome their computational hurdle, the lattice dynamics team is now ready for the SNS to test the simulation work and see if what is predicted is really there.
"Atomic-detail crystal dynamics calculations have not been possible before, and now we also have an experimental tool--the SNS--that will have the capability to test our simulations. We are looking forward to seeing the next generation of instruments at SNS demonstrate their talents." Smith said, humbly adding, "Hopefully, the calculations won't be too painfully off the mark."
Smith believes the SNS and its arsenal of specialized analytical instruments will be able to confirm--or contradict--what the simulations indicate.
"We appreciate that examining complicated proteins in this way will not be easy, even for SNS. However, with SNS instruments expected to be in some cases hundreds of times improved over currently existing facilities, we are confident that the neutron breakthrough is within reach," Smith said.
The work was recently published in Physical Review Letters.
Note: This story has been adapted from material provided by DOE, Oak Ridge National Laboratory.

Fausto Intilla

www.oloscience.com

Individual Differences Caused By Shuffled Chunks Of DNA In The Human Genome

Source:

http://www.sciencedaily.com/releases/2007/09/070927154931.htm

Science Daily — A study by Yale researchers offers a new view of what causes the greatest genetic variability among individuals -- suggesting that it is due less to single point mutations than to the presence of structural changes that cause extended segments of the human genome to be missing, rearranged, or present in extra copies.

"The focus for identifying genetic differences has traditionally been on point mutations or SNPs -- changes in single bases in individual genes," said Michael Snyder, the Cullman Professor of Molecular, Cellular & Developmental Biology and senior author of the study, which was published in Science Express. "Our study shows that a considerably greater amount of variation between individuals is due to rearrangement of big chunks of DNA."
Although the original human genome sequencing effort was comprehensive, it left regions that were poorly analyzed. Recently, investigators found that even in healthy individuals, many regions in the genome show structural variation. This study was designed to fill in the gaps in the genome sequence and to create a technology to rapidly identify structural variations between genomes at very high resolution over extended regions.
"We were surprised to find that structural variation is much more prevalent than we thought and that most of the variants have an ancient origin. Many of the alterations we found occurred before early human populations migrated out of Africa," said first author Jan Korbel, a postdoctoral fellow in the Department of Molecular Biophysics & Biochemistry at Yale.
To look at structural variants that were shared or different, DNA from two females -- one of African descent and one of European descent -- was analyzed using a novel DNA-based methodology called Paired-End Mapping (PEM). Researchers broke up the genome DNA into manageable-sized pieces about 3000 bases long; tagged and rescued the paired ends of the fragments; and then analyzed their sequence with a high-throughput, rapid-sequencing method developed by 454 Life Sciences.
"454 Sequencing can generate hundreds of thousands of long read pairs that are unique within the human genome to quickly and accurately determine genomic variations," explained Michael Egholm, a co-author of the study and vice president of research and development at 454 Life Sciences.
"Previous work, based on point mutations estimated that there is a 0.1 percent difference between individuals, while this work points to a level of variation between two- and five-times higher," said Snyder.
"We also found 'hot spots' -- particular regions where there is a lot of variation," said Korbel. "While these regions may be still actively undergoing evolution, they are often regions associated with genetic disorder and disease."
"These results will have an impact on how people study genetic effects in disease," said Alex Eckehart Urban, a graduate student in Snyder's group, and one of the principal authors on the study. "It was previously assumed that 'landmarks,' like the SNPs mentioned earlier, were fairly evenly spread out in the genomes of different people. Now, when we are hunting for a disease gene, we have to take into account that structural variations can distort the map and differ between individual patients."
"While it may sound like a contradiction," says Snyder, "this study supports results we have previously reported about gene regulation as the primary cause of variation. Structural variation of large of spans of the genome will likely alter the regulation of individual genes within those sequences."
According to the authors, even in healthy people, there are variants in which part of a gene is deleted or sequences from two genes are fused together without destroying the cellular activity with which they are associated. They say these findings show that the "parts list" of the human genome may be more variable, and possibly more flexible, than previously thought.
Other authors from Yale in addition to primary authors Alex E Urban and Jan Korbel, who is also affiliated with the European Molecular Biology Laboratory in Heidelberg, Germany, are Fabian Grubert, Philip Kim, Dean Palejev, Nicholas Carriero, Andrea Tanzer, Eugenia Saunders, Sherman Weissman, and Mark Gerstein. The research was funded the National Institutes of Health, a Marie Curie Fellowship, the Alexander von Humboldt Foundation, The Wellcome Trust, Roche Applied Science and the Yale High Performance Computation Center.
Citation: Science: Science Express (on line) September 28, 2007.
Note: This story has been adapted from material provided by Yale University.

Fausto Intilla

www.oloscience.com