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and activate a receptor protein - active receptor acts as a transcription factor, attaching to specific sites on bacterium's DNA and changing activity of nearby •form biofilms es bacterial cells that stick to one another and to their substrate Sending ligand → cell chemical messengers relay the signal spreads through the human body receptor of the target cell → response or non-target cell, no receptor for ligand Endocrine signaling • long-distance · horomones carry Signals to target cells ex) humans release thyrold and gohads circadian Rhythm: telling 24 hr day/night cycle Photoperiodism: different clock telling seasons target genes 4.2 Mechanisms of signal transduction pathways Purpose of signaling respond to environmental cues • energy conservation- use certain abilities only when needed . Broad steps D signal reception - receptor protein fits ligand ↑ ligand es often found in the membrane/ cytoplasm ligand has to fit receptor ↑ receptor light waves signal coming from the enut, chemical (ex, food kinase 2) transduction SHAPE CHANGE es convert external signal to change in internal cell activity ligand causes receptor to change shape @opens binding site for next step in pathway proteins are activated a) kinase-phosphorylate next protein, Phosphatase-out phosphate off protein, inactivation b) transport protein- organelle membrane in eukaryotic cell release new chemical inside the cell to activate the next protein activated transport protein releases and messenger bind to next protein es gets its shape changed active site is opened, substrate bigger to smaller d) enzyme activated enzyme combines -shape changes. ↳ chemical diffuse out of organelle to oy to plasm → Lind to allosteric site of the next protein. c) enzyme- activated enzyme cuts up chemical, small product activates next protein -P, allesteric site Tnext protein to change its shape → new binding site ¿ es if the ligand chemical is small and nonpolar, cross phospholipid bilayer e steroid horomone, tetastorone (hydrophobic ligand) → intercellular receptor 3) response a) activate existing protein -turn on/off a metabolic pathway - open a transport probein chemicals, larger demical activates the next protein •substrate the substrate binds to the allosteric site of transport protein enzyme P 2nd step has to cause the receptor protein to change shape. signaling pathways can also be turned off initial ligand can fall off - the receptor protein is closed and further steps are deactivated bind to receptor inside Ca²+ Ca ²+ Ca²+ speeds chemical reaction that outs off dremical ->> changes shape and diffuse calcium out of cytoplasm targeted proteins bring about a cellular response factor how often a transcription gene takes place Influence how much Protein is made b) modify rate of new protein production -final protein that will be activated at the end of the pathway is the transcription factor protein which binds to DNA certain shape DNA code class notes Bleier's Signal Transduction class notes Signal Transduction 2) Transduction Reception Reception ligandy 888 388 Transduction 33 3 Response receptor protein (usually in membrane) -2 key domains. activated next protein a) ligand-binding domain inactive receptor 2) >> 100 receptor + next protens could be kinase -> phosphorylates intracellular domain fits next step. 3) Response enzyme transport protein passing message from protein → protein next protein directly ·receptor tyrosine kinase ATP ADP ATPI (CAMP DD 27 82222 333 activate a) just. b) try to change gene expression produce or release and ---> Can Pall out 272 active messenger chemicals that bind to next protein (2nd messenger) existing inactive protein achvoka next protein. next proten → activate transcription factor protein to turn a gene on/off/up/down 4.3 Interpreting diagrams and types of feedback Negative feedback, feedback inhibition - turns itself off using the end product - negate or oppose Initial direction, maintain homeastasis Positive feed back -stimulates initial direction, increases same direction stop sign A B CID Cytokines (e.g., EPC) Cytokine Receptor JAKS A inhibits B C activates D Caspase 8 Bcl-XL 1 Cytochrome C ↓ Caspase 9 FADD Survival Factors (e.g., IGF1) FasR RTK PI3K Akt STAT3,5 Death factors (e.g. FasL, Tnf) Akka IKB Bad- Abnormality Sensor Bcl-2 PLC ↑ Cell PKC NF-KB Bim. die Apoptosis D cannot deactivate E C cannot activate D Binhibits c A inhibits B so B is still activated ex Binh Chemokines, Hormones, Transmitters (e.g., interleukins, serotonin, etc.) 1000 GPCR 100 A B C D E activates DNA Jamage G-Protein A is Inadive, so it is unable to inhibit B Therefore B is active and does its job of deactivating C C therefore cannot activate D and D cannot deactivate E, so E is active Adenylate cyclase + PKA inhibits Bax. Growth Factors (e.g., TGFa, EGF) MEKK CREB if P53 is active, it will promote stopping cell proliferation and initiating apoptosis ARF mdm2 RTK cdc42 ↓ Grb2/SOS + Ras + Raf Myc:- Mad: Max-Max + MEK MAPK Fyn/Shc MKK ERK JNKS + + Fos Jun Gene Regulation Extracellular Matrix Integrins FAK Src A has been inactivated E2F Dishevelled + GSK-33 ↓ APC B-catenin TCF B-catenin CycID Rb CDK4 Cell Proliferatione TCF p16 CyclE-p27 CDK2 p21 p15 Gli - Wnt ✓ Hedgehog Stopping cell division or proliferation and promote apotosis RTK activates PI3K once PI3K is active, it can activate both PKC and Akt Akt activates Akka and PKC activates NF-kB → ARF, mdm2, p53, pal and Bax all interact programmed cell death guardian angel of the genome by stopping cell division or cell proliferation and promote apoptosis if there is a lot of DNA damage doesn't copy the cell and pass the errors on destroy the cell if the DNA is too damaged Dog Case Study in signaling pathways Email 1 From: Melody Mikelson <[email protected]> Sent: Wednesday, November 29, 2006 12:17 pm To: Tessa Wright <[email protected]> Subject: Cell signaling pathway viagra goal T Nitroglycerin ligand Nitric Oxide Ca²+ Nitric Oxide (N:O) Nitric Oxide Synthase CaM PDE5 INHIBITORS PDE5 too low Citrulline Endothelial Or Neuronal Cell 5'-GMP L-Arginine TLOCALLY PRODUCED TMLC GTP 1 N:O-Guanylyl Cyclase (active) GC NITRIC OXIDE ginseng CGMP 2nd inessenger RELAXATION receptor Guanylyl Cyclase (inactive) MLCK MLC P'tase Phospho-Proteins receptor Lowering of Ca²+ Desensitization to Ca²+ Ca²+ SEQUESTRATION. GC P'Lamban receptor PKG MLC-P GTP Relaxation CONTRACTION CGMP Activated PKG K- IP Receptor Ca²+ RELEASE Smooth Muscle Cell Ca²+ EXPORT Ca²+ Inactive PKG Problem: dog response might be zero, or too low Ca²+ ATP ho ligand bind to GC receptor GC receptor changes shape, open up an active site domain GC bind GTP substrates + turn them into CGMP products CGMP goes to PKG + changes its shape allosteric site PKG is a kinase that phosphorylates MLC phosphate, change MLCP's shape Proteins Abbreviations: N:O: nitric oxide GTP: guanosine triphosphate CGMP: cyclic guanosi onophosphate PKG: CGMP dependent protein kinase ATP: adenosine triphosphate Viagra inhibits PDES → breaks down CGMP CGMP causes relaxation Activated PKG inhibits the intake of Calt, tregers PKG triggers reduction of cat in the toplasm PKG, also triggers MLCPtase → MLC-P relaxation Nitric oxide ames in as the first messenger that initates the ligand in the cell membrane which activates the second messenger from GC (substrate) cGMP (enzyme) to PKG. Therefore, the quantity of the response is being more amplified Abbreviations: PDE5: phosphodiesterase GC: guanylyl cyclase GTP: guanosine triphosphate (inactive form). CGMP: cyclic guanosine monophosphate (active form) 5'- GMP: hydrolyzed guanosine monophsphate (inactive form) PKG: CGMP dependent protein kinase MLC: myosin light chain MLC-P: phosphorylated myosin light chain MLC P'tase: myosin light chain phosphatase MLCK: myosin light chain kinase IP3 receptor: inositol triphosphate receptor Ca: calcium ions. P'Lamban: phospholamban BK K CHANNEL I) nitric oxide is the first ligand that inlates the signal transduction pathway 2) diagram suggests that the initial receptor is inside the smooth muscle cell cytoplasm 3) Second messenger in the pathway is CGMP 4) arrows from small to big indicates that the activates PKG, cellular response: relaxation, allows blood to flow causing erection response is being more amplified 4.4 Binary Fission and mitosis Mitosis 1) growth 2) repair 3) asexual reproduction 8 G₂ مر S Overview (steps) 1) Interphase : G₁, S, G₂ CHRO NATIN (chromosome) ←thin 23tokinesis M M ID Same genes y ·loosely packed up, accessible to be read - interphase G₁ mitosis neal to dinde prepare G₁, G₂ Gcell grows, makes proteins 2) Mitosis pack up, line up, split up DNA 3) Cybo kinesis: split up cells DNA during cell cycle Go interphase, longest SISTER CHROMATID r r TXX XT sister chromatids homologous pairs tied together cells don't need to divide, might sehd early step of interphase, Go to exit the cell cycle and keeps DNA unpacked Copy DNA →while it is still unpacked, growth, protein production more Copy DNA S end result: 2cells identicall to original cell can then repeat to make more cells →piece of DNA • packed up DNA in early mitosis -exact duplicate DNA in human body cells diploid: 2 of each chromosome = 2n Y Y=yellow seed color y= green seed color €‡. homologous pairs that haven't been copied yet YX Y y and its exact copy, tied together →never tied, together XX comes in homologous pairs . DNA synthesis R=round seed shape r= wrinkled seed shape T= tall plant t= short plant create whole new Copy of DNA while unpacked @Mitosis • chromosomes appear in sister chromatid form m SEPERATE CHROMOSOMES daughter chromosome when splitted ve one copy goes to a cell and vice versa th · homologous pairs can be slightly different, Interphase (Sphase) different alleles • Copy DNA still chromatin) Proteins X centrosome- - build spindle fibers to Connect Result: • sister chromatids Seperated -2 cell identical to original diploid (2n=8) diploid (2n=8) Cell cycle steps d+ ·centromere: DNA region holding sister chromatids together R+ rf 8 chromosomes 4 pairs X X et it initial cell (uu uu uu vu 2n=8 chromosomes 4 pairs Mitosis • chromosomes appear in sister chromotid form motor proteins help'walk' and organize them in the middle of the cell • line up as sister chromatids End cell also needs 8 chromosomes X X ·motor proteins walk chromosomes apart un packing to chromatin form, nucleus reforms 3 cytokinesis: cells seperate one cell tuo cells Bleier's Binary Fission class Notes Key vocabulary - DNA chemical codes for proteins (ATCG bases) •gene: group of lo00s of bases coding for one protein · chromosome: one physically continuous strand of DNA with looos genes (46 total) •unpacked loase form: chromatin ↳only time we can access genes - packed up for splitting replicated sister chromatids ↳ should be identical (unless tied in x shape mutation) also comes in pairs in diploid body cells (1 from mom, 1 from dow) → homologous pairs Goal of any cell division prokaryotes: binary fission eukaryotes mitasis Prophase 12 Steps of Mitosis od when chromosomes are first packed into sister chromatid form and the nucleus begins to disappear prophase: nucleus and nucleolus disappear; chromosomes appear as two identical, connected sister chromatids; mitotic spindle, made of microbules, begins to form; contrioles move to opposite poles of the cell (plant cells do not have controles) metaphase: middle; sister chromatids line up along the middle of the cell, ready to split apart anaphase: apart; the split sister chromatids move via microtubules to the opposing poles of the cell- the chromosomes are pulled to opposite poles by the spindle apparatus. After anaphase, each pole of the cell has a Complete set of chromosomes belophase: the mudei for the newly split cells form; the hudeoli reappear, and the chromatin uncoils the Metaphase Apoptosis is programmed cell destruction le some genes in same locations, but might be different alleles of those genes is to make sure product calls have all the different chromosomes Anaphase DIGITIK Telophase → motor proteins هم (O) (O) Interphase chromosomes begin to unpack back to chromatin form and the nucleus begins to reform 4.5 Regulation of mitosis why regulate mitosis? -resource-intensive (nucleotide, ATP, specialized protein) between G and S phase +P CDK + E, cDk4 +D · G₁ = •CYCD + CYCE @ between G₂ and mitosis Different checkpoints · G₂M checkpoint: cdk4/cyclin B replication completed - - DNA Integnty Key Proteins Proto-oncogenes kb can't inhibit DNA replication stimulate cell division problem: overactive might lead to cancer controlled by ook and cyclin always present but default function is inactive CDK + y clin = active . Spindle checkpoint Apc (metaphase) chromosomes attached at metaphase plate specific cyclins are made at specific times . · G₁/s check point - end of signaling pathway encourage moving on in the cell aycle past checkpoints Tumor suppressor genes · discourage cell division can't fix apoptosis damaged cell DNA mutated, cancer is processed Apoptosis is programmed cell death · used to rid the body of cells that have been damaged beyond repair • provents cancer If apoptosis is prevented, it can lead to uncontrolled cell division and the subsequent development of a tumor 4.5 Extra Resources Normal cells - know when to divide Cell division is regulated -regulation saves resources CDNA nucleotides, ATP amino acids) Different checkpoints G, checkpoint control whether to do mitosis or not G₂M checkpoint - do mitosis correctly cyclin accumulation Role of Environment - ligands that trigger pathways -growth factors stimulate mitosis - contact inhibition triggers inhibition of mitosis Causes of Cancer 6 VS. - DNA code for proteins get messed up (mutation) - genes: mutations that increase odds of knockout mutation in life - environment : exposure to mutagens . radi ation chemical Different types of cancer ·benign: tends to stay local malignant: may metastasize around body ल if a cell receives a go-ahead signal, the cell continues if a cell does not receive, the cell exits the cell cycle and goes into Go, a nondividing state treatment local surgery Cancer cells do not stop dividing broken signaling pathways cydins and cyclin-dependent kinases (CDK) -cyclin builds up at the right time to activate cok, which activates other proteins to move past a checkpoint - cytoplasmic elements trigger progress past checkpoint Potential cause of cancer pathways that stimulate mitosis are overactive •P53 (protein) activates pathway to inhibit mitasis if there is ONA damage • pathways that inhibit mitosis are broken and do not work chemotherapy: chemicals attack dividing cells (side effect) challenge: cancer cells are own body colls gone wrong, difficult to target