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Cancer researchers found a new mechanism potentially explaining evolution of signalling pathways
February 08, 2006Cancer researchers at the University of Helsinki, in trying to find a novel tumor suppressor gene, instead found an important evolutionary change that occurred in a key developmental signalling pathway. The finding suggests a potential mechanism for evolution of complex intercellular signalling pathways.
A relatively small number of evolutionary conserved genes are responsible for controlling the development of the diverse range of animal species. Most of these genes have been originally identified in fruit fly, based on the analysis of mutations that alter the body pattern of a developing embryo.
During embryonic development, cells regulate the growth and differentiation of each other by secreting extracellular signalling molecules (growth factors or morphogens), which bind to receptors present on the surface of other cells. The receptors in turn activate intracellular signalling pathway composed of proteins that relay the signal to the nucleus, activating specialized proteins called transcription factors. The transcription factors then affect expression of genes that induce cell growth and differentiation.
The signal transduction molecules and mechanisms of major developmental signalling pathways are thought to be evolutionary conserved between invertebrates and vertebrates in such a way that if a signalling pathway is present in a given organism, it includes all the major classes of components found in humans. Because of the lack of intermediate forms, the evolution of these complex signalling pathways is not understood in detail, and the emergence of signalling pathways with multiple specific and essential components has even been used as an argument against evolution.
Because multiple components of the Hedgehog (Hh) signalling pathway are defective in human cancers, Markku Varjosalo in Professor Jussi Taipale's laboratory (the University of Helsinki and National Public Health Institute of Finland) cloned the gene for mammalian homolog of a key regulator of fruit fly Hh signalling pathway, Costal-2. However, further analysis of the function of the mammalian gene revealed that it did not function as a Hh pathway regulator, let alone as the tumor suppressor gene the researchers had hoped for. Instead, together with a group led by Prof. Rune ToftgÃård and Dr. Stephan Teglund from Karolinska Institutet, the researchers found that another gene (Suppressor of Fused), which has a minor role in Hh signalling in fruit fly is critical for Hh pathway regulation in mammals.
The finding is the first clear demonstration of a major difference in the function of conserved signalling pathways between species. The results also show that multi-component pathways evolve, in part, by the insertion of novel proteins between existing pathway components. This insertion mechanism can potentially explain a challenging aspect of evolutionary biology regarding the emergence of signalling pathways with multiple specific components.
University of Helsinki
The signal transduction molecules and mechanisms of major developmental signalling pathways are thought to be evolutionary conserved between invertebrates and vertebrates in such a way that if a signalling pathway is present in a given organism, it includes all the major classes of components found in humans. Because of the lack of intermediate forms, the evolution of these complex signalling pathways is not understood in detail, and the emergence of signalling pathways with multiple specific and essential components has even been used as an argument against evolution.
Because multiple components of the Hedgehog (Hh) signalling pathway are defective in human cancers, Markku Varjosalo in Professor Jussi Taipale's laboratory (the University of Helsinki and National Public Health Institute of Finland) cloned the gene for mammalian homolog of a key regulator of fruit fly Hh signalling pathway, Costal-2. However, further analysis of the function of the mammalian gene revealed that it did not function as a Hh pathway regulator, let alone as the tumor suppressor gene the researchers had hoped for. Instead, together with a group led by Prof. Rune ToftgÃård and Dr. Stephan Teglund from Karolinska Institutet, the researchers found that another gene (Suppressor of Fused), which has a minor role in Hh signalling in fruit fly is critical for Hh pathway regulation in mammals.
The finding is the first clear demonstration of a major difference in the function of conserved signalling pathways between species. The results also show that multi-component pathways evolve, in part, by the insertion of novel proteins between existing pathway components. This insertion mechanism can potentially explain a challenging aspect of evolutionary biology regarding the emergence of signalling pathways with multiple specific components.
University of Helsinki
Signalling Pathways Current Events and Signalling Pathways News RSSReducing p38MAPK levels delays aging of multiple tissues in lab mice
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New oncogene gives valuable insight into hepatocellular tumors in humans
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Combining targeted therapy drugs may treat previously resistant tumors
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Cancer-causing gut bacteria exposed
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New results help predict treatment response in colorectal cancer
Genetic testing can identify a group of patients with advanced colorectal cancer who are likely to survive on average twice as long if treated with the drug cetuximab, late breaking results show.
HSP90: New point of view on melanoma of the eye, at the MUHC
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Targeting gut bugs could revolutionize future drugs, say researcher
Revolutionary new ways to tackle certain diseases could be provided by creating drugs which change the bugs in people's guts, according to a Perspective article published today in the journal Nature Reviews Drug Discovery.
Manchester researchers announce new methods of beating breast cancer
University of Manchester researchers will reveal new ways of controlling and treating breast cancer at the National Cancer Research Institute conference in Birmingham today (Monday 1 October 2007).
Minimum information standards -- all for 1 and 1 for all
Three papers published by EMBL scientists and their collaborators will make it much easier to share and compare information from large-scale proteomics data. The papers are published in Nature Biotechnology on 8th and 26th August.
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Signalling Pathways in Apoptosis (Modern Genetics , Vol 5) by Diane Watters (Author), Martin Lavin (Author) Apoptosis, or programmed cell death, is a necessary process by which a cell may die without adversely affecting its environment. It plays a crucial role in normal development, and in the body's defence mechanisms against disease. Too much cell death is destructive, leading to neurodegenerative diseases and impaired development. Conversely, too little cell death can lead to an increased susceptibility to cancer and sustained viral infection. Apoptosis is a matter of balance-a balance which is sustained or offset by various signaling pathways within the cell. Dramatic progress has been made in the study of apoptosis over the past decade. One of the most rapidly expanding knowledge bases being established is on the molecular mechanisms controlled by a variety of gene products including... |
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Jnk Signalling Pathway by Annning Lin (Author) Insulin-like growth factors are ubiquitously expressed and are crucial for growth and function of almost all cells. Together with their binding proteins and receptors, they form a widely studied biological system involving many proteins and characterized by complex interactions. In addition to its significance in growth and development, the insulin-like growth factor system also has important roles in a wide variety of pathological states. This has led to interest in the therapeutic potential of insulin-like growth factors and their binding proteins as candidate drug targets. This comprehensive book contains current information on both basic science and clinical aspects of IGFs and their regulatory proteins, with emphasis on their relevance to cancer. | |
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Signalling Pathways in Acute Oxygen Sensing (Novartis Foundation Symposia) by Novartis Foundation (Author) Oxygen sensing is a key physiological function of many tissues, but the identity of the sensor, the signalling pathways linking the sensor to the effector, and the endpoint effector mechanisms are all subjects of controversy. This book evaluates the various mediators that have been proposed, including the mitochondria, NAD(P)H oxidases, cytochrome p450 enzymes, and direct effects on enzymes and ion channels. There has been a resurgence of interest in the role of mitochondria, based partly on the ability of mitochondrial inhibitors to mimic hypoxia, but there is little consensus concerning mechanisms. Some favour the view that the primary signalling event is a reduction in cell redox state and reactive oxygen species (ROS) due to general inhibition of the electron transport chain (ETC);... |
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Phosphoinositide 3-kinase Signalling Pathway: The Key to Cell Proliferation And Death by Eric W-F Lam (Author) Imperial College, London, UK. Provides a detailed description of the structure and mechanisms of phosphoinositide 3-kinase (P13Ks) signalling of all classes. Topics include cell proliferation, cell death, phosphoinositide 3-kinase signalling pathways, P13K signalling to cell survival, and more. For researchers. Expanded-outline format. |
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Cellular Integration of Signalling Pathways in Plant Development (Nato a S I Series Series H, Cell Biology) by Italy) NATO Advanced Study Institute on Plant Cell and Molecular Biology (8th : 1997 : Acquafredda di Maratea (Author), Fiorella Lo Schiavo (Editor), North Atlantic Treaty Organization. Scientific Affairs Division (Editor) In the last few years there have been tremendous advances in the understanding of signals and signalling pathways that operate at the cellular level and lead to developmental processes. In 27 chapters, this volume investigates the cellular and molecular basis of plant development. It highlights the most recent progress on signals, machinery, and pathways in the plant cell. Emphasis is placed on integrating these studies with those on cell division, cell plate formation, and other aspects of plant development, in order to elucidate the intricate relationships between them. |
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Cell Apoptotic Signalling Pathways by Charles O. Pickens (Editor) Apoptosis is the regulated form of cell death. It is a complex process defined by a set of characteristic morphological and biochemical features that involves the active participation of affected cells in a self-destruction cascade. This programmed cell death plays a critical role in physiological functions such as cell deletion during embryonic development, balancing cell number in continuously renewing tissues and immune system development.Additionally, a dysregulation of apoptosis is underlying in numerous pathological situations such as Parkinson, Alzheimer's disease and cancer. A number of studies have pointed out an association between consumption of fruits and vegetables, and certain beverages such as tea and wine, which are rich in polyphenols, with reduced risk of chronic... |
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Mammalian cell cycle checkpoints: signalling pathways and their organization in space and time [An article from: DNA Repair] by J. Lukas (Author), C. Lukas (Author), J. Bartek (Author) This digital document is a journal article from DNA Repair, published by Elsevier in 2004. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: The major mission of the cell division cycle is a faithful and complete duplication of the genome followed by an equal partitioning of chromosomes to subsequent cell generations. In this review, we discuss the advances in our understanding of how mammalian cells control the fidelity of these fundamental processes when exposed to diverse genotoxic insults. We focus on the most recent insights into the molecular pathways that link the sites of DNA lesions with the cell cycle machinery in specific phases of the cell cycle. We... |
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The Involvement of Lipoxygenases in Inflammatory Signalling Pathways of Human Sebocytes in Vitro by Theodosios Alestas (Author) ?cne is a common disease affecting the majority of young people. The inflammation in the sebaceous gland plays a major role in the pathogenesis of acne. Lipoxygenases form a family of lipid peroxidising enzymes. Among lipoxygenases, the functions of 5-lipoxygenase are well understood thanks to the implication of leukotrienes. Leukotriene B4 is the most potent pro-inflammatory mediator. We demonstrate that sebocytes, cells full of lipids, express both 5- and 15-lipoxygenase. Moreover leukotriene B4 as well pro-inflammatory cytokines are released by sebocytes after lipoxygenase activation. Human sebocytes possess the enzyme machinery to produce leukotriene B4. A reduction of leukotriene B4 seems to be effective in acne skin lesions and thereafter able to anameliorate acne. |
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