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Cell Communications https://www.yout ube.com/watch?v =W-1UfjdSbgo Overview Signal reception and the initiation of transduction Transduction pathways Cellular responses to signals http://www.bio.miami.edu/dywang/150lec-10.html http://www.youtube.com/watch?NR=1&v=tMMrTRnFdI4 Overview of Cell Signaling Proximity is a factor Local regulators are nearby cells 1) paracrine signaling 2) synaptic signaling Hormones are long distance signals Reception, transduction and response https://www.youtube.com/watch?v=tkguTfVqvsM http://www.hhmi.org/bulletin/february-2012/prialt-paralyzes-fish http://www.hhmi.org/bulletin/february-2012/prialt-blocks-painsignaling-mice Stages of cell signaling Glycogen depolymerization by epinephrine 3 steps: •Reception: target cell detection •Transduction: single-step or series of changes •Response: triggering of a specific cellular response Signal reception and the Initiation of Transduction Chemical signals (ligands) bind to receptor proteinchanges shape Most receptors are plasmamembrane proteins 1)Tyrosine-kinase receptors 2) G-protein-linked receptors 3)Ion-channel receptors https://www.youtube.com/watch?v=NXOXZkaSVI http://www.youtube.com/watch?v=V_0EcUr_txk&feature=related Second Messengers http://www.youtube.com/watch?v=K7WSMybZeA8 In response to a signal relayed by a signal transduction pathway, the cytosolic calcium level may rise, usually by a mechanism that releases Ca2 from the cell’s ER. The pathways leading to calcium release involve still other second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). These two messengers are produced by cleavage of a certain kind of phospholipid in the plasma membrane. https://www.youtube.com/watch?v =2bbBrpgeheY Signal Transduction Pathways Relay signals from receptors to responses Protein phosphorylation major mechanism Roles of cyclic AMP, calcium ions and inositol triphosphate http://www.youtube.com/watch?v=iGb93jCKVXs&feature=related Cellular Responses to Signals Signal amplification Signal specificity Here is a simplified pathway Here is a more complete view of a signal transduction pathway involving tumor necrosis factor . cholera The cholera toxin is an enzyme that chemically modifies a G protein involved in regulating salt and water secretion. Because the modified G protein is unable to hydrolyze GTP to GDP, it remains stuck in its active form, continuously stimulating adenylyl cyclase to make cAMP. The resulting high concentration of cAMP causes the intestinal cells to secrete large amounts of salts into the intestines, with water following by osmosis through the CFTR protein “Woe to the child which when kissed on the forehead tastes salty. He is bewitched and soon will die” - old proverb apoptosis http://www.youtube.com/watch?v=9KTDzZisZ0 http://www.youtube.com/watch?v=v1PWcX 66ucI&feature=related The molecular mechanisms underlying apoptosis were worked out in detail by researchers studying embryonic development of a small soil worm, a nematode called Caenorhabditis elegans. The timely suicide of cells occurs exactly 131 times during normal development of C. elegans, at precisely the same points in the cell lineage of each worm. The main proteases of apoptosis are called caspases In humans and other mammals, several different pathways, involving about 15 different caspases, can carry out apoptosis. The pathway that is used depends on the type of cell and on the particular signal that initiates apoptosis. http://www.youtube.com/watch?v=jo8gx61BR-Y P53- tumor suppressor http://www.youtube.com/watch?v=RxwYoevYZYs p53 (also known as protein 53 or tumor protein 53), is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. http://www.youtube.com/watch?v=iGQdwSAAz9I Proto-oncogenes and Oncogenes Oncogenes arise when protooncogenes mutate or are moved (or amplified) to a part of the genome where their expression is greatly heightened. The BCR-ABL fusion gene causes chronic myelogenous leukemia. The experimental drug STI 571 competes with ATP to block the action of the fusion protein, thus stopping the cancer. http://www.emp iregenomics.co m/shop/BCRABL1-FISHProbe.html http://www.youtube.c om/watch?v=dpgxB9 xXIHs Scientists have divided oncogenes into the 5 different classes Growth factors These genes produce factors that stimulate cells to grow. Growth factor receptors These genes are normally turned "on" or "off" by growth factors. Certain mutations in the genes that produce these cause them to always be "on." In other cases, the genes are amplified. As a result, the cells become overly sensitive to growth-promoting signals. Signal transducers These are the intermediate pathways between the growth factor receptor and the cell nucleus where the signal is received. Transcription factors These molecules act on the DNA and control which genes are active in producing RNA and protein Programmed cell death regulators The abnormal production of these molecules prevent a cell from committing suicide when it becomes abnormal HER2 (human epidermal growth factor receptor 2) is a protein that plays an important role in how cells grow, multiply, and survive. HER2 is produced by the HER2/neu gene. Normal cells contain two copies of the HER2 gene and make amounts of HER2 to allow normal cell growth and division. Some cancer cells, however, contain many more copies of the HER2 gene and in turn produce too much HER2 protein. This "overexpression" of HER2 receptors results in a cancer that is "HER2+." Trastuzumab (Herceptin) is a drug called a monoclonal antibody that has been approved for use by the FDA. It works by preventing the HER2/neu protein from promoting excessive growth of cancer cells. Human Epidermal growth factor Receptor 2 Monoclonal antibodies are antibodies that are identical because they were produced by one type of immune cell, all clones of a single parent cell. Given any substance, it is possible to create monoclonal antibodies that specifically bind to that substance The tissue culture cells made from fusion of a plasma cell, which is the antibody producer and the myeloma cell, which provides longevity and ability to make large amounts of antibody http://www.youtube.com/watch?v=4NH2ldNPeRo http://www.youtube.com/watch?v=lcHy8THENXo