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Strahl B.D.,Lineberger Comprehensive Cancer Center
Nature Communications | Year: 2014

Histone modifications are major determinants of DNA double-strand break (DSB) response and repair. Here we elucidate a DSB repair function for transcription-coupled Set2 methylation at H3 lysine 36 (H3K36me). Cells devoid of Set2/H3K36me are hypersensitive to DNA-damaging agents and site-specific DSBs, fail to properly activate the DNA-damage checkpoint, and show genetic interactions with DSB-sensing and repair machinery. Set2/H3K36me3 is enriched at DSBs, and loss of Set2 results in altered chromatin architecture and inappropriate resection during G1 near break sites. Surprisingly, Set2 and RNA polymerase II are programmed for destruction after DSBs in a temporal manner - resulting in H3K36me3 to H3K36me2 transition that may be linked to DSB repair. Finally, we show a requirement of Set2 in DSB repair in transcription units - thus underscoring the importance of transcription-dependent H3K36me in DSB repair. © 2014 Macmillan Publishers Limited.

Bottom Line: Uninsured women under age 65 were more likely than insured women to experience delays between an initial positive screening mammogram and a diagnostic follow-up. Journal in Which the Study was Published: Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research. Author: Louise M. Henderson, PhD, an assistant professor in the Department of Radiology at the University of North Carolina Chapel Hill and a member of the UNC Lineberger Comprehensive Cancer Center. Background: About 10 percent of women who undergo screening mammograms are referred for additional follow-up imaging, which could include a diagnostic mammogram, breast ultrasound, MRI, or a breast biopsy, Henderson explained. Guidelines from the Centers for Disease Control and Prevention recommend that women with a positive screening mammogram receive a follow-up diagnostic workup within 60 days of the initial positive screen. Delays in follow-up may contribute to disparities in breast cancer outcomes, as they have been associated with larger tumor size at diagnosis and reduced survival. How the Study Was Conducted: This study sought to examine the effect of insurance status on the time between the initial screening mammogram and the diagnostic follow-up procedure. Using data from the Carolina Mammography Registry, a North Carolina population-based registry of breast imaging and cancer outcomes, Henderson and colleagues identified women with a positive screening mammogram, and analyzed the receipt of follow-up by insurance status and age group. Among 43,026 women included in the study, 73 percent were under 65 years of age and 27 percent were 65 or older. In the under-65 age group, 89 percent had private insurance, 3 percent were uninsured, and the remainder had a combination of Medicare and private insurance. Results: The study showed that uninsured women less than 65 years of age experienced a longer time to the start of diagnostic follow-up, and were 59 percent more likely to miss the CDC guideline than privately insured women in the same age group. In this age group, nearly 18 percent of women without insurance received their diagnostic follow-up after 60 days compared with 11 percent of women with private-only insurance. Among women 65 or older, there were no statistically significant delays. Henderson noted that in many cases, the difference in follow-up time was small. For the overall study population, the median time to follow-up was 12 days. Among women under 65, those with no insurance had a median follow-up time of 16 days, compared with 12 days among women with private-only insurance. However, she said the median time may mask more significant delays from some women, and noted that approximately 10 percent of women received no follow-up within a year of their initial positive screening mammogram. In women less than 65 years with no insurance, almost 14 percent had no follow-up within the year, compared with 11 percent of women with private- only insurance. Author Comment: "The women with no insurance are consistently a little bit behind in terms of follow-up, and we need to work toward addressing that gap to ensure better outcomes for these women," Henderson said. Henderson said that several factors could be responsible for the differences in time between initial positive screening and follow-up diagnostic tests. For example, she noted, women with private insurance may be more economically advantaged, with better access to care. "If a woman experiences a positive screening mammogram and is called back for a follow-up diagnostic test, it's important that it gets taken care of in a timely fashion," Henderson said. "We want to encourage women to be aware that an abnormal result in a screening mammogram is not necessarily an emergency, but it must be resolved." Study Limitations: Henderson said a limitation of the study is that insurance status was self-reported and may not be accurate. Also, certain personal factors like anxiety and stress, which have been shown to affect follow-up time, were outside the scope of this study. Funding & Disclosures: This study was funded by grants from the National Institutes of Health. Henderson declares no conflicts of interest. To interview Louise M. Henderson, please contact Julia Gunther at or 215-446-6896. For a photo of Henderson, click here. Visit our newsroom. About the American Association for Cancer Research Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 37,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and patient advocates residing in 108 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 30 conferences and educational workshops, the largest of which is the AACR Annual Meeting with almost 19,500 attendees. In addition, the AACR publishes eight prestigious, peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual investigator grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and other policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www. .

News Article | November 21, 2016

Edison T. Liu, M.D. of The Jackson Laboratory (JAX) has been named a Fellow of the American Association for the Advancement of Science (AAAS). Elected by his peers, Liu was recognized for his distinguished contributions to cancer biology, particularly the molecular analysis of breast cancer, and to the global advancement of human genomics. "I am honored to be elected as an AAAS Fellow, and to be included in this distinguished group of leaders dedicated to advancing science," said Liu. "This is a pivotal moment in medical science -- one where the global community can work together as never before in improving human health." Liu is the president and CEO of The Jackson Laboratory. Previously, he was the founding executive director of the Genome Institute of Singapore, and served as president of the Human Genome Organization (HUGO). Prior to that position, Liu was the scientific director of the National Cancer Institute's Division of Clinical Sciences, where he led the intramural clinical translational science programs. As a faculty member at the University of North Carolina at Chapel Hill, Liu was the director of the UNC Lineberger Comprehensive Cancer Center's Specialized Program of Research Excellence in Breast Cancer; the director of the Laboratory of Molecular Epidemiology at UNC's School of Public Health; chief of Medical Genetics; and the chair of the Correlative Science Committee of the national cooperative clinical trials group, CALGB. Dr. Liu's scientific research focuses on the functional genomics of human cancers, particularly breast cancer, uncovering new oncogenes, and deciphering on a genomic scale the dynamics of gene regulation that modulate cancer biology. He obtained his B.S. in chemistry and psychology, as well as his M.D., at Stanford University, and served his internship and residency at Washington University's Barnes Hospital in St. Louis, followed by an oncology fellowship at Stanford. This year, 391 members were selected as Fellows because of their scientifically or socially distinguished efforts to advance science or its applications. The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a National Cancer Institute-designated Cancer Center, a facility in Sacramento, Calif., and a genomic medicine institute in Farmington, Conn. It employs 1,800 staff, and its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health. For more information, please visit http://www. . About the American Association for the Advancement of Science The American Association for the Advancement of Science (AAAS) is the world's largest general scientific society and publisher of the journal Science as well as Science Translational Medicine, Science Signaling, a digital, open-access journal, Science Advances, Science Immunology, and Science Robotics. AAAS was founded in 1848 and includes nearly 250 affiliated societies and academies of science, serving 10 million individuals. Science has the largest paid circulation of any peer-reviewed general science journal in the world. The non-profit AAAS is open to all and fulfills its mission to "advance science and serve society" through initiatives in science policy, international programs, science education, public engagement, and more. For the latest research news, log onto EurekAlert! , the premier science-news Web site, a service of AAAS. See http://www. .

News Article | March 11, 2016

UNC Lineberger Comprehensive Cancer Center researchers have discovered that a deficiency in a key protein that regulates immune system warning signals could be a new biomarker for colorectal cancer, the second largest cancer killer in the United States. They believe the marker could be used to gauge response to a potential new treatment for the disease. In the journal Cell Reports, researchers reported they found markedly low levels of the protein NLRX1 in multiple laboratory models of colorectal cancer, and in samples of human tissue. Studies have shown that the protein is known to be involved in regulating immune system signals in order to prevent hyperactive inflammatory responses by the immune system. The UNC Lineberger researchers believe their finding also points to a role for the protein in preventing colorectal cancer growth. Based on their findings, they believe they’ve identified a potential treatment for colorectal cancer with low NLRX1. “What we’re proposing is, if you can profile people with low NLRX1 in their colorectal cancer, you could consider using this therapy that we identified,” said the paper’s senior author Jenny P. Ting, Ph.D., a University of North Carolina Lineberger member and the William R. Kenan Jr. Professor of Microbiology and Immunology at the UNC School of Medicine. “We have identified a critical biomarker for this disease.” The protein NLRX1 helps keep immune system responses in-check by downregulating signals that help trigger a wider immune response. A. Alicia Koblansky, Ph.D., the paper’s first author and a postdoctoral research fellow at UNC Lineberger, said they believe the protein is involved in dampening immune signals that could harm the host. In the UNC Lineberger-led study, researchers studied the effect of deleting NLRX1 in preclinical models of sporadically-growing colorectal cancer. They tested the effect in an animal model with mutations in the APC (Adenomatous polyposis coli) gene. Koblansky said about 80 percent of human colon cancer tumors have a mutation in this gene. The mutation is known to lead to spontaneous growth of colon cancer tumors. The loss of NLRX1 revealed a dramatic increase in tumor growth as well as an increase in activation of signaling pathways known to help drive cancer. Additionally, they found significantly lower expression of NLRX1 in human colon cancer cell samples compared to normal cells. They also studied multiple public databases of colon cancer samples, finding decreased expression of NLRX1 in each. The findings reinforced their belief that NLRX1 normally helps to keep a check on colorectal cancer. The researchers believe the findings can have treatment implications, since they know that NLRX1 limits activation of signals that help trigger other cancer-driving growth signals. To that end, they tested a drug, already approved as a treatment for arthritis, that’s designed to block one of the downstream pathways normally down-regulated by NLRX1. They found that the drug, which blocked a small signaling protein called IL-6, decreased tumor growth and activation of downstream cancer-causing signals. Based on these findings, they believe IL-6 blockers could be redirected against colorectal cancers with low NLRX1 expression. “We’re arguing that clinicians could analyze NLRX1 expression, and provide them with a more targeted treatment based on that finding,” Koblansky said. “We want to help clinicians to drive precision medicine for patients as much as possible.” This project was supported in part by National Institute of Health, and by the American Cancer Society.

News Article | December 6, 2016

This week's edition of PLOS Medicine, featuring four Research Articles and two Perspectives, begins a special issue devoted to research on cancer genomics. Research and discussion papers selected along with two leaders in the field, Guest Editors Elaine Mardis and Marc Ladanyi, will highlight progress in the study of important cancer types, and assess the clinical implications of progress in this fast-moving field. In their Perspective article, James Topham and Marco Marra discuss the acquisition of genetic information from tumors, which in recent years has progressed from localized analyses of single genes, and subsequently panels of genes, that are important in specific cancer types, to whole-genome sequencing. Intensive effort is being applied to analyses of tumor genomes aimed at selection of appropriate therapies for individual patients, and the authors emphasize the need to study the dynamic nature of tumor genome sequences -- which can change over time and adapt to cytotoxic and other treatments -- to maximize the potential benefit for patients. In a Research Article, Dr. Charles Perou of the University of North Carolina's Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA and colleagues study the evolution of tumors in two patients with triple-negative, basal-like breast cancer, a disease associated with lack of estrogen receptor, progesterone receptor, and HER2 which generally results in poor clinical outcome. For many cancer types, it is the metastases, or the spread of cancer cells from the original tumor to other parts of the body, that are life-threatening, and it is therefore of interest to study the cancer after it has left the site of origin. The researchers studied whole-genome sequence and gene expression information from primary tumors and metastases obtained from the patients at autopsy, and report similar somatic mutation and copy number patterns across all tumors in an individual patient. This analysis identified multiple populations of cells, or clones, in the original tumor as well as in the metastatic sites. The findings suggest that metastatic potential is established early in the trajectory of this form of breast cancer, and that multiple clones from the primary tumor traveled together to distant organs. Anindya Dutta and colleagues present a study of gene expression changes in large datasets derived from patients with brain tumors in a second Research Article -- focusing on low-grade gliomas and glioblastoma multiforme, which is a particularly intractable form of the disease. The authors study expression of large numbers of long noncoding RNAs (lncRNAs), which are thought to be involved in governing the expression of other genes and thereby controlling important processes such as development and tumorigenesis. The authors found that a signature made up of selected lncRNAs was associated with length of survival in patients with low-grade gliomas. If validated in future work, these findings could lead to a way to estimate prognosis for patients with this type of tumor, which might be useful in planning treatment. Further research and discussion articles addressing important topics in the area of cancer genomics will appear throughout the December, 2016 issue of PLOS Medicine. No specific funding received for this article. The authors have declared that no competing interests exist. IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER:http://journals. This study was supported by funds from the following sources: the Breast Cancer Research Foundation (LAC); the National Institutes of Health (NIH) (LAC, M01RR00046); National Cancer Institute P50-CA58223 Breast SPORE Program (LAC); National Cancer Institute P50-CA58223 Breast SPORE Program (CMP); National Cancer Institute R01-CA195754-01 (CMP); National Cancer Institute R01-CA148761 (CMP); the Breast Cancer Research Foundation (CMP); National Cancer Institute F30-CA200345 (MBS); and the National Human Genome Research Institute Center Initiated Projects U54HG003079 (ERM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. I have read the journal's policy and the authors of this manuscript have the following competing interests: CMP is an equity stock holder of BioClassifier LLC and University Genomics, and ERM, CMP, and JSP have filed a patent on the PAM50 subtyping assay. ERM served as guest editor on PLOS Medicine's Special Issue on Cancer Genomics. Hoadley KA, Siegel MB, Kanchi KL, Miller CA, Ding L, Zhao W, et al. (2016) Tumor Evolution in Two Patients with Basal-like Breast Cancer: A Retrospective Genomics Study of Multiple Metastases. PLoS Med 13(12): e1002174. doi:10.1371/journal.pmed.1002174 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America Department of Mathematics, Washington University in St. Louis, St. Louis, Missouri, United States of America Division of Hematology/Oncology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER:http://journals. The study was funded by the National Cancer Institute grants P01 CA104106 and R01 CA166054 to AD. BJR was supported by training grants T32 GM007267 and T32 CA009109. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist. Reon BJ, Anaya J, Zhang Y, Mandell J, Purow B, Abounader R, et al. (2016) Expression of lncRNAs in Low-Grade Gliomas and Glioblastoma Multiforme: An In Silico Analysis. PLoS Med 13(12): e1002192. doi:10.1371/journal.pmed.1002192 Department of Pathology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America Department of Biochemistry, University of Virginia, Charlottesville, Virginia, United States of America Division of Neuro-Oncology, Neurology Department, University of Virginia Health System, Old Medical School, Charlottesville, Virginia, United States of America IN YOUR COVERAGE PLEASE USE THIS URL TO PROVIDE ACCESS TO THE FREELY AVAILABLE PAPER:http://journals.

DALLAS--(BUSINESS WIRE)--The 2016 recipients of the Brinker Awards for Scientific Distinction will be recognized for their vital contributions to research today at the prestigious 39th annual San Antonio Breast Cancer Symposium (SABCS). Charles Perou, Ph.D. and Monica Morrow, M.D., FACS, will both deliver keynote lectures during the symposium, and will be honored at a reception this evening. Established by Komen in 1992, the Brinker Awards for Scientific Distinction recognize the efforts of pioneers in two critically important areas of the fight to end breast cancer: Clinical Research and Basic Science. This year’s winners join the ranks of an esteemed group of scientists who have been recognized for advancing breast cancer research and medicine with the Brinker Awards – the highest scientific honor awarded by Susan G. Komen, the world’s leading breast cancer organization. The 2016 Brinker Award for Scientific Distinction in Basic Science will be presented to Dr. Perou, the May Goldman Shaw Distinguished Professor of Molecular Oncology and Professor of Genetics and Pathology & Laboratory Medicine at the University of North Carolina School of Medicine and co-program leader of the breast cancer research program and member of the UNC Lineberger Comprehensive Cancer Center. Dr. Perou’s work has helped to characterize the diversity of breast tumors, demonstrating that breast cancers can be classified into at least five molecular subtypes. His work also led to the discovery of the basal-like/triple-negative breast cancer (TNBC) subtype. Further, he and his colleagues were among the first to discover that the breast cancer subtypes were of prognostic and predictive value, and to associate specific genetic mutations with specific breast cancer subtypes. Dr. Morrow, chief of the Breast Surgery Service and Anne Burnett Windfohr Chair of Clinical Oncology at Memorial Sloan Kettering Cancer Center and Professor of Surgery at Weill Cornell Medical College, will receive the Brinker Award for Scientific Distinction in Clinical Research. Dr. Morrow has been a champion of the idea that “more is not necessarily better” when it comes to breast cancer treatments, devoting her career to advancing clinical practice and empowering women to make treatment decisions. She was instrumental in showing that sentinel lymph node dissection is an effective and safe alternative to complete (axillary) lymph node dissection for many women with early metastatic breast cancer. More than 60 other Komen representatives including Scientific Advisory Board members, Komen Scholars and grantees will join Dr. Perou, Dr. Morrow and thousands of other leading physicians and researchers from around the globe at SABCS, contributing to discussions around experimental biology, etiology, prevention, diagnosis and therapy of breast cancer. Advancing breast cancer research has been a priority for Komen since opening its doors in 1982. To date, Komen has invested more than $920 million in breast cancer research, and is the largest nonprofit funder of breast cancer research outside of the U.S. government, currently funding nearly 300 research grants worldwide. Susan G. Komen is the world’s largest breast cancer organization outside of the federal government, funding more breast cancer research than any other nonprofit while providing real-time help to those facing the disease. Since its founding in 1982, Komen has funded more than $920 million in research and provided more than $2 billion in funding to screening, education, treatment and psychosocial support programs. Komen has worked in more than 60 countries worldwide. Komen was founded by Nancy G. Brinker, who promised her sister, Susan G. Komen, that she would end the disease that claimed Suzy’s life. Visit or call 1-877 GO KOMEN. Connect with us on social at

News Article | September 21, 2016

How a cell transitions from the G1 phase of the cell cycle to the S phase – a fundamental process of cell division for all eukaryotic cells on Earth – has been a long-studied question in biology. Now UNC School of Medicine scientists discovered that this boundary is regulated by a pair of large enzyme complexes that attack each other in turn to form a molecular switch, which eventually allows the cell cycle to enter into S phase. The discovery, published in today in Cell Reports, raises the possibility that future drugs could target this enzyme interaction to help stop the uncontrolled division of cancerous cells. Above all, though, it illuminates the workings of one of the most important processes in biology. “Our work describes a key piece of the puzzle for how this fundamental process works,” said Michael J. Emanuele, PhD, study senior author, assistant professor in department of pharmacology, and member of the UNC Lineberger Comprehensive Cancer Center. “We did not focus on suppressing cancer cell division in this study, but given what we’ve found we think it’s definitely worth investigating further.” The crossing from G1 to S phase is effectively a point of no return for a cell. Once past that threshold it must divide or die trying. Whereas in G1 phase the cell merely ramps up its production of proteins and other key molecules so that the two future daughter cells will have enough to live. Later, in S phase, the cell becomes committed to the division process by duplicating and then separating all of its chromosomes. Standing guard at this boundary between phases is a molecular machine known as APC/C, which comprises more than a dozen separate proteins including an enzyme component. Other scientists found that APC/C teams up with a protein called Cdh1 to grab a bunch of other proteins in the cell and tag them (with enzymes) for disposal by a roving protein-cruncher known as the proteasome. Cells commonly use tagging-for-disposal complexes like APC/C – which are known as E3 ubiquitin ligases – to regulate the amounts of specific proteins. The proteins that APC/C suppresses include many that would facilitate the cell’s entry into S-phase. Thus, while APC/C remains active, the cell cannot move into S-phase. “Shutting off APC/C is essential for cells to get across the G1/S border,” Emanuele said. “We’ve known that for a really long time, and we’ve also known that this requirement exists in the cells of all organisms from yeast to humans. But just how APC/C is shut off to permit this border crossing has not been clear.” The journey to their discovery began when Emanuele’s lab found that APC/C and Cdh1 target a protein called cyclin F. The finding was interesting because cyclin F does what Cdh1 does; it serves as a target-recognition device for another disposal-tagging E3 ubiquitin ligase, in this case one called SCF. Thus, one big ubiquitin ligase, APC/C-Cdh1, effectively shuts down SCF-cyclin F. Emanuele and his team soon found hints that SCF-cyclin F returns the favor. “When we looked at cells going through the cell cycle, we saw cyclin F levels starting to increase right at the G1/S transition, and at the same time the levels of Cdh1 were decreasing. The timing was perfect,” Emanuele said. “Then, when we put the protein complexes in cells at the same time, the levels of both went down, as if they were targeting each other.” Further experiments confirmed that while APC/C-Cdh1 targets cyclin F and thus shuts down SCF/cyclin F, the latter reciprocally targets Cdh1 and thus shuts down APC/C-Cdh1. It is that second “flip of the switch” that permits the cell’s entry into S-phase. “To the best of our knowledge nobody else has described a system involving direct antagonism between two E3 ubiquitin ligases,” Emanuele said. “It suggests the possibility that similar mutually antagonistic pairs of E3s regulate other oscillating systems in biology.” Precisely how APC/C establishes dominance to prevent S phase, and how SCF/cyclin F gets the upper hand to permit S phase, isn’t yet clear. However, cells do have a variety of systems for the dynamic control of protein activity, such as phosphorylation, which can change a protein’s shape and thereby render it active or inactive. Emanuele suspects that phosphorylation or some similar modification may be what triggers the ascendancy of each of these ubiquitin ligases in turn. “That’s something we’re working on now,” he said. The research illuminates new pathways of investigation into other cell division mysteries, including how cell division goes out of control in cancer. “Cdh1 is a largely under-appreciated tumor suppressor,” Emanuele said. “Although it blocks S phase, Cdh1 isn’t mutated in cancers. One of the implications of our data, however, is that Cdh1 is degraded at this critical G1/S juncture. It could be that in some cases, too much Cdh1degradation is all that’s needed to promote cancerous growth.”

In countries undergoing nutrition transition and historically poor minority groups in wealthy countries, obesity tends to be more common in women than men. A potential contributor to this female excess of obesity is a mismatch between perinatal nutritional restriction and a later calorie-rich environment. Several epidemiologic and quasi-experimental studies support a gender-differential effect of early nutritional deprivation on adult obesity. The quasi-experimental studies are of particular interest because results of quasi-experimental studies are typically less vulnerable to confounding bias than observational studies. Four quasi-experimental studies-exploiting 20th century famines that occurred in Europe, Africa, and Asia-provide evidence that perinatal nutritional restriction followed by relative caloric abundance may increase adult obesity risk to a greater extent in women than men. If the findings are accurate and generalizable to contemporary food environments, they suggest that the female offspring of poor, or otherwise nutritionally restricted, women in rapidly developing and wealthy countries may be at particularly high risk of adult obesity. Research into gender-specific effects of early life nutritional deprivation and its interactions with later environmental exposures may provide insight into global gender differences in obesity prevalence. © 2012 The Obesity Society.

Bankaitis V.A.,Lineberger Comprehensive Cancer Center | Mousley C.J.,Lineberger Comprehensive Cancer Center | Schaaf G.,University of Tübingen
Trends in Biochemical Sciences | Year: 2010

Lipid signaling pathways define central mechanisms for cellular regulation. Productive lipid signaling requires an orchestrated coupling between lipid metabolism, lipid organization and the action of protein machines that execute appropriate downstream reactions. Using membrane trafficking control as primary context, we explore the idea that the Sec14-protein superfamily defines a set of modules engineered for the sensing of specific aspects of lipid metabolism and subsequent transduction of 'sensing' information to a phosphoinositide-driven 'execution phase'. In this manner, the Sec14 superfamily connects diverse territories of the lipid metabolome with phosphoinositide signaling in a productive 'crosstalk' between these two systems. Mechanisms of crosstalk, by which non-enzymatic proteins integrate metabolic cues with the action of interfacial enzymes, represent unappreciated regulatory themes in lipid signaling. © 2009 Elsevier Ltd. All rights reserved.

News Article | December 21, 2016

Scientists have had few good methods for manipulating and investigating G-protein signaling. Now, UNC scientists have developed small proteins called peptides that selectively block a certain type of G-protein signaling. The peptides comprise a unique and powerful tool for studying this type of signaling and the processes in cells that depend on it. Based on this initial work, published in the Journal of Biological Chemistry, the researchers are now making related peptides that can block other types of G-protein signaling. Aside from their value as basic scientific research tools, these peptides will be used to develop potential drugs for diseases involving abnormal G-protein signaling, including a form of melanoma for which there is currently no cure. "These peptides should be valuable for drug design and discovery, and for understanding fundamental aspects of cellular biology," said John Sondek, PhD, senior author of the JBC paper and professor in UNC's departments of pharmacology and biochemistry & biophysics. G-proteins work as a sort postal service hub within the cell. They receive signals from outside the cell via partner receptors on the cell surface, and G-proteins help deliver those signals to their proper destinations within the cell. These signals are vital for proper cell function and, as a result, proper overall health of the individual. G-proteins sit on the inside of the cell membrane, close to their partner receptor. They exist in a complex made of three related subunit proteins: Gα, Gβ, and Gγ. An incoming signal from the partner receptor "activates" this complex causing the Gα subunit protein to separate from the other two. This activated form of Gα can then interact with various molecular partners to send signals deep into the cell. In humans and other mammals, there are four main families of Gα proteins, each with its own set of downstream signaling partners. Although nearly a third of modern medicines work by targeting receptors that signal via G-proteins, researchers have not had very good tools for studying the signaling pathways that run downstream of G-proteins. In this project, Sondek and his colleagues successfully fashioned one such tool - a peptide that selectively blocks an important class of Gα proteins, Gαq, from interacting with its downstream signaling partners. The team crafted the peptide using clues from structural studies of one of Gαq's known signaling partners. The peptide essentially mimics the binding region on the signaling partner. In further work funded through a new NIH grant, the Sondek lab has been developing versions of the peptide that bind even more tightly to Gαq. The researchers also plan to use the same strategy employed in this project to make peptides that selectively inhibit the other main Gα protein families, Gαs, Gαi, and Gα12. One way to use such peptides is to block the signaling that runs through the Gα protein, to see what happens in a cell when that signaling is lost and thereby learn what that signaling normally does. Another method is to genetically combine the peptide with a special fluorescent protein, in effect "lighting up" peptide-bound copies of the Gα subtype. "In this way, we can see in real time where exactly these activated Gα proteins are working in cells and how many of them there are," said Sondek, who is also a member of the UNC Lineberger Comprehensive Cancer Center. The peptides can also be used for drug discovery. Scientists can screen collections of small organic molecules - the type of molecules needed for pill-based drugs - to find any that compete with the peptides by binding tightly to Gα proteins and preventing them from transmitting signals. Those that do may be developed into potential Gα-blocking drugs. In principle, the peptides themselves can be used as Gα-blocking drugs, although they usually can't be delivered in pill form. Given the importance of G-protein signaling in cells, studies of downstream signaling pathways with the new Gα-blocking peptides are likely to reveal many new targets for future drugs, Sondek said. But at least one of these drug targets is already known - Gαq itself. A rare and often-fatal form of melanoma known as uveal melanoma, which originates in the eye, is typically driven by mutations to Gαq's gene, leaving the protein Gαq in an always-active form. A drug that simply blocks Gαq signaling may therefore help patients with this illness, which spreads beyond the eye in half of known cases. Once the cancer metastasizes, patients do not respond well to existing treatments. "This is one of our major goals," Sondek said, "to figure out how to inhibit that always-active Gα protein in uveal melanoma." He and his team, in collaboration with pharmaceutical company AstraZeneca, are currently using the new peptides to discover Gαq-blocking compounds that might be developed into treatments for this form of cancer. Sondek hopes ultimately to extend this line of research to find blockers of other proteins that are related to G-proteins but have other important roles in cells. These include the Ras cell-growth proteins, mutated versions of which are among the most common and relentless drivers of several kinds of cancer. Explore further: How to reset a diseased cell

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