Biosignaling - Creightonchemistry.creighton.edu/~jksoukup/lec13STUD.pdf · Biosignaling Cells -...

BiosignalingCells - receive and act on signalsSignal brings about response

Types of signals:Autocrine -Paracrine -Endocrine -

Lots of signals but just a few evolutionarily conserved mechanismsto detect signals and transduce them into change in cell

Weak interactionsReceptor cell-specificHigh affinity of receptors for signalCooperativity

BiosignalingTypes of signal transducers

BiosignalingI. Ligand-gated Ion Channel

Nicotinic Acetylcholine receptoropens in response to neurotransmitter acetylcholine and to nicotineFound in neurons and muscle fibers

Receptor = Allosteric proteinCooperative binding of Ach

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BiosignalingII. Receptor Enzymes

Insulin ReceptorLigand-binding domain on extracellular surface of plasma membraneEnzyme active site on cytosolic side

nucleus

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BiosignalingII. Receptor EnzymesInsulin Receptor

BiosignalingIII. G protein-coupled Receptors and Second Messengersβ-Adrenergic Receptor

a.k.a. AdrenalineRegulates metabolism in muscle, liver and fatBreakdown of glycogen and fat

Serpentine receptor - 7 transmembrane helices

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BiosignalingIII. G protein-coupled Receptors and Second MessengersEpinephrine

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BiosignalingIV. Steroid receptorsAct in nucleus to alter gene expressionSteroid hormones (estrogen, progesterone, cortisol, etc.) hydrophobicReceptors (proteins) and HREs (hormone response elements inDNA)

BiosignalingIV. Steroid receptorsReceptor for estrogenBreast cancer - some types need estrogen present for tumor growthTamoxifen = antagonist of estrogenTamoxifen competes with estrogen for binding to receptorTamoxifen has no effect on gene expression like estrogen does

RU486 = antagonist of progesteroneCompetes with prog for binding to receptorProg needed for proper implantation of fertilized ovum in uterus

BiosignalingOncogenes, Tumor Suppressor Genes, Programmed Cell Death

Tumors --> result of uncontrolled cell division - biosignaling goneBAD!Oncogenes --> a cancer-causing gene, any of several mutant genesthat cause cells to exhibit rapid, uncontrolled proliferationDiscovered in tumor-causing virusesVery similar to normal genes in the body called proto-oncogenes(growth regulating genes)

BiosignalingOncogenes, Tumor Suppressor Genes, Programmed Cell Death

Truncated version of EGF receptorOncogenic form

BiosignalingOncogenes, Tumor Suppressor Genes, Programmed Cell Death

Tumor Suppressor Genes --> encode proteins that normallyrestrain cell division, mutation in one or more can lead to tumorgrowthp53 - mutated in 90% skin cancers, 50% all other cancersRb - mutated in retinoblastoma

BiosignalingOncogenes, Tumor Suppressor Genes, Programmed Cell Death

Tumor Progression

Adenomaous polyposis coli (TS gene)

Ras (oncogene)

Deleted colon carcinoma (TS gene)

p53 (TS gene)

BiosignalingOncogenes, Tumor Suppressor Genes, Programmed Cell Death

Programmed Cell Death (Apoptosis) --> cell brings about its owndeath and lysis, signaled from outside or programmed in its genes,by systematically degrading its own macromoleculesWhen?Development of embryo (fingers)Anti-self antibodies presentMenstruationStressed cells (virus-infected to prevent infection, heat, UV light)

Mutation to any of theseproteins can lead to cancers