INTRODUCTION PART 2

1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signaltransduction INTRODUCTIONPART 2

3. Intracellular receptor signaling Signal Outside of cell Plasma membrane Cytoplasm Receptor Chaperone protein Nucleus Inside of cell

4. Ligandsbindingtointracellularreceptors CH3 CH3 CH2OH O H3C CH3 C O C OH OH HO CH3 Retinoicacid I I NH2 O O CH HO O C CH2 Cortisol OH I I Thyroxine

5. Steroid receptor superfamily Estrogen receptor 553 1 Progesterone receptor 1 946 Glucocorticoid receptor 777 1 1 Thyroidhormone receptor 408 Retinoidacid receptor 1 432 General primarystructure NH2 COOH Variableregion (≈100-500 aa) DNA binding domain (≈68 aa) Ligandbinding domain (≈225-285 aa) Aminoacid identity 0% 42-94% 15-57%

6. Glucocorticoid receptor phosphorylation • GR phosphorylationsites: • Thr171 – Glycogensynthase kinase-3 (GSK-3) • Ser 224 and 232 – Cyclin-dependentkinases(CDK) • Ser246 – JNK • Thr547 – p38 - MAPK → GCR inhibition Ser 232 Thr 171 Ser 224 Ser 246 1 2 3 4 5 Thr 547

7. GC hormonemechanisms Nongenomic GC effects Genomic GC effects Glucocorticoid mGR Plasmamembrane Cytoplasm Specific mGR dependent effects TF Nonspecific GC effects cGR Specific cGR dependent effects STAT NFkB TCR Transmembranecurrents Phosphorylationevents Calciumlevels IL-2 IkB MAPK pGRE GRE nGRE Transactivation Transrepression Slow Medium slow Rapid

8. HormonesareclassifiedintothreecategoriesbasedontheirstructureHormonesareclassifiedintothreecategoriesbasedontheirstructure • Peptides: Comprisesmost hormones, includingthosesecretedbythehypothalamus, anterior and posteriorpituitary, pancreasandparathyroid. • Amines: Derivedfromtheaminoacid, tyrosine, and includethehormonessecretedbythethyroidgland, andadrenalmedulla. Adrenomedullaryhormonesarecalledcatecholamines. • Steroids: Neutrallipidsderivedfromcholesterol; includehormonessecretedbytheadrenalcortex, ovaries and testes. Steroid and thyroidhormonesarelipidsoluble (lipophilic).

9. Primaryhormone-secretingglands • Pituitarygland(anteriorpituitary) secretes GH which is a protein stimulatingproteinsynthesis and growth (depressionatbottom of skulljust over back of roofofmouth) • Hypothalamus • Pinealglandsecretesmelatonin, a modifiedaminoacidtohypothalamusforsleep

10. The otherhormone-secretingglandsare: • Sex organs (gonads) • Ovaries:androgens and progesterones • Testes:androgens • Adrenalglands • Adrenalmedullasecretesepinephrine, norepinephrine, modifiedaminoacidsstimulatefight-or-flightresponse (increaseheart, redistributebloodtomuscles, raisebloodsugar) • Adrenalcortexsecretesglucocorticoids (cortisol), steroidstargetingmuscles, immunesystem, and othertissuestomediateresponsetostress, reducemetabolism of glucose, increasemetabolismofproeins and fats, reduceinflammationandimmuneresponses • Thyroidglandsecretescalcitonin, which is a peptideactingonbonestostimulateboneformation and lowerbloodcalcium, parathyroidraisesbloodcalcium • Pancreassecretsinsulin and glucagon

11. OtherChemicalmessengers • Cytokines • Interferonsareproteinsreleasedwhen a cell has beenattackedby a virus. Theycauseneighboringcellstoproduceantiviralproteins. Onceactivated, theseproteinsdestroythevirus • Prostaglandinsarefattyacidsthatbehaveinmanywayslikehormones. Theyareproducedby most cellsinthe body and actonneighboringcells • Pheromonesarechemicalsignalsthattravelbetweenorganisms, ratherthanbetweencellswithin an organism. Intheanimalworld, pheromonesareheavilyusedto mark territory, signalprospectivemates and tocommunicate. The presence of a pheromoneasa human sex attractant has notbeenestablished

12. Basic characteristics of cytokines • Low molecular weight (10-40 kDa) glycoproteins • Isolated cells secrete them, due togene activation • They mediate cell-cell interaction: • Sending information • Regulation of immune response • Mechanism of action: • Produced after transient gene activation • Actthrough receptorstriggeringsignaltransduction • High affinity • Picomolarconcentration • They act mostly locally

13. Environmental stimuli as signal initiators • Microbialproducts:viralnucleotides, bacteriallipopolysaccharidesstimulate TLR, and protein antigens B cell and T cellreceptors • Physicalstimuli:lightstrikingcellsinthe retina of theeye, odorantsbindingtoodorantreceptorsinthenasalepithelium, bitter and sweettastesstimulatingtastereceptorsinthetastebuds

14. Toll-likereceptors(TLRs) • Theyaresingle, membrane-spanning, non-catalyticreceptorsthatrecognizestructurallyconservedmoleculesderivedfrommicrobes. • Theyreceivetheirnamefromtheirsimilaritytothe protein codedbythe Toll geneidentifiedinDrosophilain 1985 byChristianeNüsslein-Volhard. The geneinquestion, whenmutated, makesthe Drosophila flieslookunusual, or 'weird'. The researchersweresosurprisedthattheyspontaneouslyshouted out inGerman "Dasist ja toll!" whichtranslatesas "That´s wild„.

15. TLR types LPS dsRNA LBP TLR2 TLR4 MD2 TLR9 TLR7 TLR3 CD14 MDA-5 RIG-1 TBK1 IKKe IPS1 MyD88 MyD88 JAK2 PI3K p38 JNK mTOR MyD88 TRIF PKA TAK1 PKR MKKs lkB p50 p65