Class Note for BIOC 460 at UA 2
Class Note for BIOC 460 at UA 2
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Date Created: 02/06/15
Dr Roger Miesfeld Bioc 460 Spring 2005 Signal Transduction 1 Describe how epinephrine coordinately controls glycogen degradation and glycogen synthesis in response to imminent danger What molecular mechanism regulates the onoff activity ofthe two key enzymes in glycogen metabolism 2 Epidermal growth factor EGF hormone signaling stimulates cell division by activating an intracellular phosphorylation cascade mediated by the GTP binding protein Ras Explain why mutations in Ras that block its intrinsic GTPase activity result in cancer cell division even when hormone is not bound to the EGF receptor 3 Name the two peptide hormones that are most responsible for regulating blood glucose levels in humans and briefly describe the primary function of each 4 The phosphatidylinositol 3kinase Pl3K pathway is activated by insulin signaling in liver cells Describe the key signaling events in this pathway beginning with insulinstimulation of insulin receptortyrosine kinase activity that lead to glucose uptake 5 How are G proteinmediated hormone signals turned off when hormone levels decrease outside the cell 6 Why is Gleevac STl571 such an effective anticancer drug for the treatment of chronic myelogenous leukemia CML without the side effects of other drugs 7 What role do receptortyrosine kinases have in cancer 8 How does the biochemical function ofan oncogenic Ras protein differ from a normal Ras protein with regard to signal transduction and cell growth control 9 What is the biochemical mechanism of sildena l Viagra one of a class of drugs used to treat erectile dysfunction What quotupstreamquot signal is required for sildena l to be effective 10 Why does treatment with the steroid antagonist tamoxifen block estrogen signaling in breast cancer cells but not inhibit gluconeogenesis in the liver Dr Roger Miesfeld Bioc 460 Spring 2005 Answers 1 Epinephrine binding to the epinephrine receptor betaadrenergic receptor stimulates adenylate cyclase and production of cyclic AMP through G protein coupled receptor mechanism Protein kinase A is activated by cyclic AMP binding which leads to activation of glycogen phosphorylase via activation of phosphorylase kinase and inactivation ofglycogen synthase Thus epinephrine coordinately activates glycogen degradation and inhibits glycogen synthesis The mechanism of this onoff switch is phosphorylation control 2 EGF signaling normally stimulates exchange of GDP for GTP to produce the active form of Ras RasGTP and cleavage of GTP by the intrinsic Ras GTPase converts it back to the inactive RasGDP form However mutations in the Ras GTPase that block Ras inactivation result in formation ofa constitutive quotactivatedquot Ras even in the absence of upstream EGF signaling 3 Insulin is the quotfed statequot hormone and it stimulates glucose uptake and glycogen synthesis in liver and muscle insulin also inhibits gluconeogenesis in liver Glucagon is the quothunger hormonequot and it stimulates glycogen breakdown and gluconeogenesis in the liver glucagon also inhibits glycogen and fatty acid synthesis 4 Insulin binding to the insulin receptor activates an intrinsic tyrosine kinase activity which leads to phosphorylation of IRS protein insulin receptor substrate IRS binds to and activates PI3K which phosphorylates PIP2 phosphatidylinositol 45bisphosphate located on the cytoplasmic side ofthe plasma membrane to generate PIP3 phosphatidylinositol 345triphosphate PIP3 is an anchor forthe PH pleckstrin homology domain proteins PDK1 phosphoinositol dependent kinase and PKB protein kinase B which results in the phosphorylation and activation of PKB by PDK1 Phosphorylation of PKB causes it to dissociate from PIP3 and diffuse through the cytosol where it activates GLUT4 glucose transporter translocation to the membrane and regulates enzymes controlling glycogen synthesis 5 G proteinmediated hormone signals are turned off by the intrinsic GTPase activity of G proteins which converts the active GTPG protein complex into an inactive GDPG protein complex In the absence of further hormone stimulation the GDPbound G alpha subunit remains in the inactive state associated with beta gamma subunits 6 Gleevac is a speci c inhibitor ofthe BcrAbl kinase which is a oncogenic fusion protein expressed in CML leukemia cells Since the genetic mutation that leads to the production ofthe BcrAbl fusion protein does not occur in normal cells and Gleevac does not bind to the normal cAbl kinase the drug is highly speci c and has very few side effects 7 Normally receptor tyrosine kinases transmit extracellular hormone signals to the cytosol by stimulating a kinase cascade Ifthe tyrosine receptor kinase is defective as it often is in cancer cells inappropriate signals are sent to the cell stimulating cell division even in the absence of hormones These defective tyrosine receptor kinases are often truncated due to mutations 8 Oncogenic ras protein lacks intrinsic GTPase activity and therefore is always in the GTP bound active conformation resulting in constitutive signal transduction causing uncontrolled cell growth Normal ras protein becomes inactivated by GTP hydrolysis after the removal of growth factor signals 2 Dr Roger Miesfeld Bioc 460 Spring 2005 9 Silden l Viagra is an inhibitor ofthe enzyme cyclic GMP cGMP phosphodiesterase which hydrolyzes cGMP thereby decreasing stimulation of cGMPdependent protein kinase G which is a signaling molecule required for vasodilation Sildena l only works if NO signaling is intact which is necessary to activate guanylyl cyclase and produce cGMP 10 Tamoxifen is an estrogen antagonist that binds with high af nity to the estrogen receptor and blocks estrogen signaling in breast cancer cells Tamoxifen does not bind to the glucocorticoid receptor which controls gluconeogenesis in the liver
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