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Refusal of suicide order: Why tumor cells become resistant
June 24, 2008Cells with irreparable DNA damage normally induce programmed cell death, or apoptosis. However, this mechanism often fails in tumor cells so that transformed cells are able to multiply and spread throughout the body. Scientists at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now discovered a possible cause of this failure. Tumor cells simply degrade a protein that triggers apoptosis in the case of DNA damage. Blocking this protein degradation might set apoptosis back in operation and, thus, increase the effectiveness of radiotherapy or chemotherapy. The researchers have now published their results in Nature Cell Biology.
Proteins that trigger programmed cell death, or apoptosis, must be kept under careful control. After all, a cell should induce its own death only if its genetic material is damaged so severely that there is a danger of its transformation into a malignantly growing tumor cell. However, minor damages in the DNA can be corrected by the cell's special repair mechanisms - hence, no reason to commit suicide!
Among the proteins that trigger apoptosis after severe DNA damage is the HIPK2 molecule. Scientists in Dr. Thomas Hofmann's research group at the German Cancer Research Center (DKFZ) have now shown that although HIPK2 is continuously produced in healthy cells, it is instantly degraded again. An enzyme called Siah-1 attaches labels to HIPK2 marking it as "garbage". Thus, the cell prevents that apoptosis is induced "accidentally".
Slightly damaged cells enter a kind of alarm status: They block degradation of HIPK2 by Siah-1 for a short time. But as soon as the damage is repaired, the cell immediately resumes labeling HIPK2 as garbage and degrades the molecule. Only in severely damaged cells, such as by a broken DNA double strand, degradation of HIPK2 by the Siah-1 enzyme is blocked permanently. As a result, HIPK2 accumulates, apoptosis is triggered, and the cell commits suicide.
Researchers assume that this could be one of the reasons why radiation therapy or chemotherapy is sometimes ineffective. Both treatment methods cause severe damage to tumor cells, which eventually leads to programmed cell death. "If resistances occur, this is often caused by tumor cells 'refusing' to take the order to commit suicide," Thomas Hofmann explains.
To prevent HIPK2 degradation, Hoffmann and his colleagues conducted experiments in which they blocked the Siah-1 enzyme. As a result, HIPK2 was able to accumulate even in cells that were only slightly damaged, and apoptosis was induced. "Cancer medicine might be able to make use of our discovery," speculates Hofmann. "For example, we could use a Siah-1 blocker simultaneously with chemotherapy or radiotherapy to get the cells back into the apoptosis program."
Helmholtz Association of German Research Centres
Slightly damaged cells enter a kind of alarm status: They block degradation of HIPK2 by Siah-1 for a short time. But as soon as the damage is repaired, the cell immediately resumes labeling HIPK2 as garbage and degrades the molecule. Only in severely damaged cells, such as by a broken DNA double strand, degradation of HIPK2 by the Siah-1 enzyme is blocked permanently. As a result, HIPK2 accumulates, apoptosis is triggered, and the cell commits suicide.
Researchers assume that this could be one of the reasons why radiation therapy or chemotherapy is sometimes ineffective. Both treatment methods cause severe damage to tumor cells, which eventually leads to programmed cell death. "If resistances occur, this is often caused by tumor cells 'refusing' to take the order to commit suicide," Thomas Hofmann explains.
To prevent HIPK2 degradation, Hoffmann and his colleagues conducted experiments in which they blocked the Siah-1 enzyme. As a result, HIPK2 was able to accumulate even in cells that were only slightly damaged, and apoptosis was induced. "Cancer medicine might be able to make use of our discovery," speculates Hofmann. "For example, we could use a Siah-1 blocker simultaneously with chemotherapy or radiotherapy to get the cells back into the apoptosis program."
Helmholtz Association of German Research Centres
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Demon Seduction Starring: Demon Seduction Directed By: Greg Lewolt An epic and bloody battle for the survival of planet Earth is on. Scientists experiment on a synthesized human-alien hybrid with new advanced DNA. A dying race of aliens must have the Super-DNA to continue building their population and they will stop at nothing to get it. Not wanting to bring attention to their mission, they morph into human females to seduce the scientists and obtain the secret formula. But if hot love making doesn t get the job done, the aliens will start gruesome, gut-ripping carnage and destroy all of man-kind. |
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Matrix Logics DNA System Shaping Mousse 8.47oz by Matrix Matrix Logics Color DNA System Shaping Mousse volumizes your hair with a long, lasting hold. Lightly conditions and protects hair from UV and heat styling damage. Logics Shaping Mousse volumizes hair with a clean boost of body and shine. Free form foam sculpts style with workable, lasting hold, lifts without stiffness and lightly conditions for smooth control. |
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Free-Radical-Induced DNA Damage and Its Repair: A Chemical Perspective by Clemens von Sonntag (Author) Understanding of the molecular basis of DNA damage and its repair has increased dramatically in recent years, and substantial knowledge now exists concerning the products arising from free-radical attack on DNA. Free-radical DNA damage may lead to mutations, cancer, and cell death. Free radicals have various sources, notably ionizing radiation and oxidative stress. In radiotherapy for cancer and with some anticancer drugs, use is made of cell death by excessive DNA damage. The mechanisms leading to products of free-radical attack which have been studied in models and with small double-stranded DNA fragments are discussed in detail, and the basics of the underlying free-radical chemistry are dealt with in separate chapters. |
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Technologies for Detection of DNA Damage and Mutations by G.P. Pfeifer (Editor) ''Useful and timely.'' ---Mutagenesis ''Of considerable value.'' ---Journal of Medical Genetics ''Quite readable....a comprehensive overview....perfectly covers the needs of those researchers who have to decide on the best strategy to identify damage or mutations at the molecular level.'' ---Trends in Cell Biology ''The formats of the presentations are uniform and ample and up-to-date references are provided at the end of each chapter...will be welcomed by postgraduate researchers of all ages and should retain its usefulness for a long time.'' ---Endeavour, 21(4), 1997 This important resource thoroughly reviews a wide range of techniques used in mutagenesis research--ranging from established techniques to recently developed methodologies--based on the polymerase chain... |
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DNA Damage Recognition by Wolfram Siede (Editor), Yoke Wah Kow (Editor), Paul W. Doetsch (Editor) Stands as the most comprehensive guide to the subject—covering every essential topic related to DNA damage identification and repair. Covering a wide array of topics from bacteria to human cells, this book summarizes recent developments in DNA damage repair and recognition while providing timely reviews on the molecular mechanisms employed by cells to distinguish between damaged and undamaged sites and stimulate the appropriate repair pathways. about the editors... WOLFRAM SIEDE is Associate Professor, Department of Cell Biology and Genetics, University of North Texas Health Science Center, Fort Worth. He received the Ph.D. degree (1986) from Johann Wolfgang Goethe University, Frankfurt Germany. YOKE WAH KOW is Professor, Department of Radiation Oncology, Emory... |
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Progress in DNA Damage Research by Souta Miura (Editor), Shouta Nakano (Editor) This book presents the latest research on DNA damage, which due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day. While this constitutes only 0.000165 per cent of the human genome's approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumour suppresser genes) can impede a cell's ability to carry out its function and appreciably increase the likelihood of tumour formation.The vast majority of DNA damage affects the primary structure of the double helix; that is, the bases themselves are chemically modified. These modifications can in turn disrupt the molecules' regular helical structure by introducing non-native chemical bonds or bulky adducts... |
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From DNA Damage & Stress Signalling to Cell Death Poly ADP-Ribosylation Reaction by Gilbert de Murcia (Editor), Sydney Shall (Editor) CNRS, Strasbourg, Germany. An introduction to poly-ADP ribosylation reactions, as well as comprehensive coverage of cell DNA damage-induced post-translational modifications. Also includes coverage of the pharmacological role of inhibition of PARP and future directions of research into cellular responses to DNA damage. |
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New Research on DNA Damage by Honoka Kimura (Editor), Aoi Suzuki (Editor) DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day. While this constitutes only 0.000165 per cent of the human genome's approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumour suppresser genes) can impede a cell's ability to carry out its function and appreciably increase the likelihood of tumour formation.The vast majority of DNA damage affects the primary structure of the double helix; that is, the bases themselves are chemically modified. These modifications can in turn disrupt the molecules' regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix.... |
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DNA Damage and Repair: Volume I: DNA Repair in Prokaryotes and Lower Eukaryotes (Contemporary Cancer Research) by Jac A. Nickoloff (Editor), Merl F. Hoekstra (Editor) Univ. of New Mexico, Albuquerque. Volume 1 of a 2-volume set presenting a critical review of major aspects of DNA repair in a wide variety of organisms. Illustrated. Outline format. DNLM: DNA Repair. |
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