 |
|
'Shuttling' protein possibly key to resilience of cancer cells
March 08, 2006WEST LAFAYETTE, Ind. - Researchers at Purdue University have discovered a molecular mechanism that may play a crucial role in cancer's ability to resist chemotherapy and radiation treatment and that also may be involved in Alzheimer's and heart disease.
The scientists, using an innovative imaging technique invented at Purdue, have learned that a protein previously believed to be confined to the nucleus of healthy cells actually shuttles between the nucleus and cytoplasm, the region of the cell surrounding the nucleus. Moreover, the protein's shuttling is controlled by the presence of another protein in the nucleus and its attachment to that second protein.
"Our findings may provide a new avenue for the development of innovative treatments for certain cancers and other conditions," said Chang-Deng Hu, an assistant professor in Purdue's Department of Medicinal Chemistry and Molecular Pharmacology and an investigator at the Walther Cancer Institute in Indianapolis.
The experiments were done using a line of "teratocarcinoma" malignant tumor cells from mice called F9, which, when subjected to the right biochemical signals, have the ability to alter their properties and are considered to be "cancer stem cells." The hypothetical cancer-resistance role of cancer stem cells could explain why tumors return after treatment. If stem cells prove to be critical to cancer's resistance to treatment, new medications might be developed to target cancer stem cells while chemotherapy or radiation is administered, Hu said.
Research findings are detailed in a paper appearing this month in the EMBO Journal, published by the European Molecular Biology Organization. The paper was written by postdoctoral research associate Han Liu, laboratory technician Xuehong Deng and graduate student Y. John Shyu, all in the Department of Medicinal Chemistry and Molecular Pharmacology; Jian Jian Li, an associate professor in the Department of Health Sciences; Elizabeth J. Taparowsky, a professor in the Department of Biological Sciences; and Hu.
The research focuses on two proteins called c-Jun and ATF2, which are key components of a protein complex called activating protein-1, or AP-1. AP-1 is a major "transcription factor" that binds to DNA, activating the "expression" of genes required to produce proteins needed for vital cellular processes. The proteins that make up AP-1, including ATF2 and c-Jun, often join together in the nucleus, forming either "homodimers," when two of the same proteins join, or "heterodimers," when two different proteins come together.
"Current thinking is that all of these AP-1 proteins in healthy cells are localized, or confined, to the nucleus," Hu said. "But in this work we found for the first time that ATF2 constantly shuttles between the cytoplasm and the nucleus."
The researchers found that the ATF2 protein possesses "nuclear export" and "nuclear localization" signals, which enable it to travel out of and back into the nucleus, respectively. The researchers also discovered that if ATF2 attaches to c-Jun in the nucleus, forming a heterodimer, the nuclear export signal is blocked, preventing ATF2 from traveling from the nucleus to the cytoplasm.
Researchers had already known that chemotherapy and radiation cause cancer cells to increase production of ATF2. The Purdue researchers found that "overexpressed," or overproduced, ATF2 is predominantly located in the cytoplasm because of an inadequate amount of c-Jun in the nucleus, suggesting it is likely that overexpressed ATF2 also may be localized in the cytoplasm in cancer cells, Hu said.
The Purdue researchers not only discovered that ATF2 is localized in the cytoplasm of the mouse cancer stem cells, but also that exposing the cells to ultraviolet light induced more production of c-Jun protein in the nucleus, causing the ATF2 to bind with c-Jun, stopping the shuttling process and causing cell death. The c-Jun-ATF2 heterodimers cause more c-Jun protein to be produced, attracting more ATF2 and reinforcing the localization of ATF2 in the nucleus.
Because it has been reported that ATF2 overexpression causes the resistance of cancer cells to chemotherapy and radiation, the ATF2 shuttling might play a key role in the ability of cancer cells to resist cancer treatments, and preventing the ATF2 from moving into the cytoplasm might improve the effectiveness of anticancer treatments.
"Ultimately, we are trying to figure out how to make the cancer cells more sensitive to chemotherapy and radiation treatment by keeping the ATF2 in the nucleus," Hu said.
The Purdue researchers tracked ATF2 and other proteins using a fluorescent imaging technique developed by Hu called bimolecular fluorescence complementation. The procedure involves breaking a fluorescent protein into two fragments and then fusing each fragment to different AP-1 proteins, including c-Jun and ATF2. When the proteins later bind to form a heterodimer, the fluorescent-protein fragments are reunited, causing them to glow green when illuminated with a light source. The fluorescence enabled the researchers to pinpoint the location of c-Jun-ATF2 heterodimers and discover the shuttling movements of ATF2. The ATF2 protein also has been found in the cytoplasm of diseased brain cells in Alzheimer's disease and muscle cells in the heart, suggesting the same shuttling mechanism might be involved in those conditions.
"These findings suggest a new avenue to study how ATF2 is implicated in the pathogenesis of these diseases," Hu said.
Hu and co-authors Li and Taparowsky are affiliated with the National Cancer Institute-designated Purdue Cancer Center and with the Oncological Sciences Center in Discovery Park, the university's hub for interdisciplinary research. The research has been funded by the Purdue Cancer Center, Indiana Elks Charities Inc., Walther Cancer Institute, National Institutes of Health and National Science Foundation.
Purdue University
The experiments were done using a line of "teratocarcinoma" malignant tumor cells from mice called F9, which, when subjected to the right biochemical signals, have the ability to alter their properties and are considered to be "cancer stem cells." The hypothetical cancer-resistance role of cancer stem cells could explain why tumors return after treatment. If stem cells prove to be critical to cancer's resistance to treatment, new medications might be developed to target cancer stem cells while chemotherapy or radiation is administered, Hu said.
Research findings are detailed in a paper appearing this month in the EMBO Journal, published by the European Molecular Biology Organization. The paper was written by postdoctoral research associate Han Liu, laboratory technician Xuehong Deng and graduate student Y. John Shyu, all in the Department of Medicinal Chemistry and Molecular Pharmacology; Jian Jian Li, an associate professor in the Department of Health Sciences; Elizabeth J. Taparowsky, a professor in the Department of Biological Sciences; and Hu.
The research focuses on two proteins called c-Jun and ATF2, which are key components of a protein complex called activating protein-1, or AP-1. AP-1 is a major "transcription factor" that binds to DNA, activating the "expression" of genes required to produce proteins needed for vital cellular processes. The proteins that make up AP-1, including ATF2 and c-Jun, often join together in the nucleus, forming either "homodimers," when two of the same proteins join, or "heterodimers," when two different proteins come together.
"Current thinking is that all of these AP-1 proteins in healthy cells are localized, or confined, to the nucleus," Hu said. "But in this work we found for the first time that ATF2 constantly shuttles between the cytoplasm and the nucleus."
The researchers found that the ATF2 protein possesses "nuclear export" and "nuclear localization" signals, which enable it to travel out of and back into the nucleus, respectively. The researchers also discovered that if ATF2 attaches to c-Jun in the nucleus, forming a heterodimer, the nuclear export signal is blocked, preventing ATF2 from traveling from the nucleus to the cytoplasm.
Researchers had already known that chemotherapy and radiation cause cancer cells to increase production of ATF2. The Purdue researchers found that "overexpressed," or overproduced, ATF2 is predominantly located in the cytoplasm because of an inadequate amount of c-Jun in the nucleus, suggesting it is likely that overexpressed ATF2 also may be localized in the cytoplasm in cancer cells, Hu said.
The Purdue researchers not only discovered that ATF2 is localized in the cytoplasm of the mouse cancer stem cells, but also that exposing the cells to ultraviolet light induced more production of c-Jun protein in the nucleus, causing the ATF2 to bind with c-Jun, stopping the shuttling process and causing cell death. The c-Jun-ATF2 heterodimers cause more c-Jun protein to be produced, attracting more ATF2 and reinforcing the localization of ATF2 in the nucleus.
Because it has been reported that ATF2 overexpression causes the resistance of cancer cells to chemotherapy and radiation, the ATF2 shuttling might play a key role in the ability of cancer cells to resist cancer treatments, and preventing the ATF2 from moving into the cytoplasm might improve the effectiveness of anticancer treatments.
"Ultimately, we are trying to figure out how to make the cancer cells more sensitive to chemotherapy and radiation treatment by keeping the ATF2 in the nucleus," Hu said.
The Purdue researchers tracked ATF2 and other proteins using a fluorescent imaging technique developed by Hu called bimolecular fluorescence complementation. The procedure involves breaking a fluorescent protein into two fragments and then fusing each fragment to different AP-1 proteins, including c-Jun and ATF2. When the proteins later bind to form a heterodimer, the fluorescent-protein fragments are reunited, causing them to glow green when illuminated with a light source. The fluorescence enabled the researchers to pinpoint the location of c-Jun-ATF2 heterodimers and discover the shuttling movements of ATF2. The ATF2 protein also has been found in the cytoplasm of diseased brain cells in Alzheimer's disease and muscle cells in the heart, suggesting the same shuttling mechanism might be involved in those conditions.
"These findings suggest a new avenue to study how ATF2 is implicated in the pathogenesis of these diseases," Hu said.
Hu and co-authors Li and Taparowsky are affiliated with the National Cancer Institute-designated Purdue Cancer Center and with the Oncological Sciences Center in Discovery Park, the university's hub for interdisciplinary research. The research has been funded by the Purdue Cancer Center, Indiana Elks Charities Inc., Walther Cancer Institute, National Institutes of Health and National Science Foundation.
Purdue University
Cancer Cells News and Current Cancer Cells Events RSSAtomic structure of the mammalian 'fatty acid factory' determined
Mammalian fatty acid synthase is one of the most complex molecular synthetic machines in human cells. It is also a promising target for the development of anti-cancer and anti-obesity drugs and the treatment of metabolic disorders.
M. D. Anderson study finds change in HER2 status after treatment with Herceptin
Researchers at The University of Texas M. D. Anderson Cancer Center have discovered that when treated with Herceptin prior to surgery, 50 percent of HER2 positive, breast cancer patients showed no signs of disease at the time of surgery.
NC State Is First University in Nation to Offer Canine Bone Marrow Transplants
Dogs suffering from lymphoma will be able to receive the same type of medical treatment as their human counterparts, as North Carolina State University becomes the first university in the nation to offer canine bone marrow transplants in a clinical setting.
DNA editing tool flips its target
Imagine having to copy an entire book by hand without missing a comma. Our cells face a similar task every time they divide. They must duplicate both their DNA and a subtle pattern of punctuation-like modifications on the DNA known as methylation.
New nano device detects immune system cell signaling
Scientists have detected previously unnoticed chemical signals that individual cells in the immune system use to communicate with each other over short distances.
VCU Massey Cancer Center Spearheads Novel Clinical Study for Lymphoma Patients
The Virginia Commonwealth University Massey Cancer Center recently opened a National Cancer Institute (NCI)-sponsored, phase II clinical study for certain sub-types of non-Hodgkin's lymphoma.
Too much calcium in blood may increase risk of fatal prostate cancer
Men who have too much calcium in their bloodstreams may have an increased risk of fatal prostate cancer, according to a new analysis from Wake Forest University School of Medicine and the University of Wisconsin.
New role for Natural Killers!
Scientists at the University of York have discovered a new role for a population of white blood cells, which may lead to improved treatments for chronic infections and cancer.
Variation of normal protein could be key to resistance to common cancer drug
Researchers at the Moores Cancer Center at the University of California, San Diego (UC SD) in La Jolla have found evidence explaining why a common chemotherapy drug, cisplatin, may not always work for every cancer patient. They have shown that when a variant version of a key protein that normally causes cell death is active, patients may be resistant to the cancer-killing drug.
Normalizing tumor vessels to improve cancer therapy
Chemotherapy drugs often never reach the tumors they're intended to treat, and radiation therapy is not always effective, because the blood vessels feeding the tumors are abnormal-"leaky and twisty" in the words of the late Judah Folkman, MD, founder of the Vascular Biology program at Children's Hospital Boston.
More Cancer Cells News Articles
 | Biology of Cancer by Robert A. Weinberg The Biology of Cancer is a comprehensive, authoritative, up-to-date textbook written by a major researcher in the field. It clearly presents the principles of cancer biology in an organized and accessible fashion. The information unfolds through the presentation of key experiments which give readers a sense of discovery, and provides insights into the conceptual foundation underlying cancer... |
 | One Renegade Cell: The Quest For The Origin Of Cancer (Science Masters) by Robert A. Weinberg "Cancer wreaks havoc in almost every part of the human body"--Robert Weinberg's opening remark is a chilling reminder of the pervasiveness of an all-too-familiar disease. Cancer touches most families, and if you have ever wondered why, despite so much time, effort, and money, it has proved such a seemingly intractable problem, then read One Renegade Cell, Robert Weinberg's masterful explanation.... |
 | University Physics by Hugh D. Young, Roger A. Freedman |
 | The Biological Basis of Cancer by Robert G. McKinnell, Ralph E. Parchment, Alan O. Perantoni, G. Barry Pierce, Ivan Damjanov After introducing students to the basic biological principles of cancer, this new updated edition of an established textbook progresses to the human dimensions of the disease by considering actual cases of cancer. Other chapters discuss cancer pathology, metastasis, carcinogenesis, genetics, oncogenes and tumor suppressors, epidemiology, and the biological basis of cancer treatment. Also included... |
 | Basic Clinical Radiobiology (Hodder Arnold Publication) This concise, but comprehensive textbook sets out all the essentials of the science and clinical application of radiobiology for those seeking accreditation in radiation oncology. The fully updated 3rd edition continues to discuss the basis of radiation therapy and presents the principles and significant scientific developments that underlie current attempts to improve the radiotherapeutic... |
 | Natural Obsessions : Striving to Unlock the Deepest Secrets of the Cancer Cell by Natalie Angier As dramatic as The Double Hex and as absorbing as The Soul of a New Machine, Natural Obsessions explores the advanced reaches of molecular biology, the nature of the human cell, and the genes that control cancer. It unforgettably portrays some of the best young scientists in the world, the rewards and discouragements of scientific research, and the very process of scientific... |
 | Comprehensive Handbook of Childhood Cancer and Sickle Cell Disease: A Biopsychosocial Approach Over recent decades, tremendous advances in the prevention, medical treatment, and quality of life issues in children and adolescents surviving cancer have spawned a host of research on pediatric psychosocial oncology. This important volume fulfills the clear need for an up-to-date, comprehensive handbook for practitioners that delineates the most recent research in the field--the first of its... |
 | 100 Questions & Answers About Bone Marrow and Stem Cell Transplantation by Ewa Carrier, Gracy Ledingham This text is a patient-oriented guide to dealing with a bone marrow or stem cell... |
 | Patient Number One: A True Story of How One CEO Took on Cancer and Big Business in the Fight of His Life by Rick Murdock, David Fisher Cancer is a terrorist, driving us mad with feelings of hopelessness and despair. One man, faced with lymphatic cancer and a poor prognosis, had the unique opportunity to influence not just the course of his treatment, but the research guiding that treatment. Patient Number One tells the story of Rick Murdock, former CEO of CellPro, a Seattle biotech company specializing in cell separation--as it... |
 | Tumor-Induced Immune Suppression: Mechanisms and Therapeutic Reversal There is now a pressing need to discuss the already described and newly emerging mechanisms to see how they can be put together in more or less cohesive structure and how they can help to improve immune response to tumors. This monograph will, for the first time, present a comprehensive overview of different mechanisms of immune dysfunction in cancer as well as therapeutic approaches to their... |
| © 2008 BrightSurf.com |