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Laura Francis

Stem cells and signal transduction ● What are cells? ○ There are many ways to answer that ■ Complex living systems ■ Bats of protein that make more bags of proteins (e.g. ability to independently reproduce) ● Prokaryotic do not have a nucleus whereas eukaryotic do ● Cells reproduce independently ○ “Bags of proteins that make more bags of proteins” ● How do cells know what to do, where to go, etc.? ○ Use stem cells as a model to discuss the answers to some of the questions What is a stem cell? ● “Stem cells have the remarkable potential to develop into many different cell types in the body during early life and growth. In addition, in many tissues that serve as a sort of internal repair system, dividing essentially w/o limit to replenish other cells as long as the person/animal is still alive. When a stem cell divides, each new cell has the potential either to remain a stem cell, or become another type of cell with a more specialized function, such as muscle cells, a red blood cell, or a brain cell.” ○ layman’s terms: cells that have the potential to become other cell types through differentiation ■ e.g. skin, blood, liver, brain, heart, kidney, nerve cells, and more! ■ can be used to replenish cells ■ can become a specialized cell ● or choose to remain stem cells ■ can divide ● A cell type in which its job is to divide to make more cells or differentiate into cells with specialized functions ○ e.g. heart, blood, liver, etc. ○ Yeast, amoeba are eukaryotic because they have a nucleus (single-celled organisms) Stem cells ● CAN undergo cell division ● Can become many different types of cells (e.g. have the potential to differentiate into cells w/different functions) ● stem cells make more cells ● differentiate into a specific cell type ● repairs ● adult bodies contain stem cells ● cannot duplicate once it's a specified cell ● terminally Differentiated cells ○ Cannot undergo cell division ○ Cannot differentiate any further ○ perform spec. functions in the body e.g. muscle cells or neurons or bone cells ○ does a specific function ○ different cell types are different because they express different genes ● multipotent blood stem cell--> differentiation-->red blood cell ● differentiated cells cannot duplicate because they don't receive signals ● if they do-->cancer! ● Stem cells and differentiated cells... ○ receive signals from their environment ○ have receptor proteins (binding sites) on their cell surface ○ express genes (make mRNA and proteins) ■ each express a different subset of genes ● The potency of a cell specifies its differentiation (potential to differentiate into different cell types ● Totipotency: Ability of a single cell to divide and produce all the differentiated cells in an organism, including extraembryonic (outside the embryonic body) tissues. Specialized to make a fetus ● Pluripotent: Stem cells that can give rise to any fetal/adult cell type ○ Alone they can’t develop into fetal/adult animal bc lack potential to contribute to extraembryonic tissue ● Multipotent: Progenitor cells that have the potential to give rise to cells from multiple but limited number of lineages ○ inner cells of a blastocyst is pluripotent-->become fetus ● Totipotent (early embryo)-->pluripotent-->multipotent ● Most stem cell types: DNA content doesn’t change when differentiation occurs ○ Gene expression changes ● Adult stem cells can be found in bone marrow ○ Used to tissue repair in different areas ● Induced Pluripotent Stem Cells (iPS cells) ○ Adult cells genetically reprogrammed to an embryonic stem cell-like state ○ Forced to express genes and factors important for maintaining defined properties of embryonic stem cells ■ Being studied as an alternative to using embryonic stem cells ■ Embryonic stem cells must be killed in order to be used ■ Not hard to induce embryonic to be pluripotent ● stem cell to differentiated cell: fertilized egg-->fetus ● how does this happen? How do cells know which cell type to turn into? ● Cells from another person, implanted into you, will likely be destroyed/rejected by the immune system ○ considered a foreign object bc different from your own cells ● Using your own cells shouldn’t be rejected ○ Fetus: immune system isn’t great-->doesn’t pick up embryonic stem cells receptors ○ Immune system doesn’t know receptors-->DESTROY ● Gene for the receptor could be there but not expressed ○ Not always rejected, but remains a possibility ● Autoimmune disorders: own immune system doesn’t recognize self-cells-->ATTACK ○ e.g. Multiple Sclerosis: immune system attacks myelin sheath on axons of neurons ● Adult human bodies do not contain totipotent stem cells ○ used embryonically-->pregnant women would have ● Hematopoietic stem cells CAN differentiate into neurons ○ de-differentiate the cells to iPS-->diff into neuron ● Stem cells divide, terminally differentiated cells don’t ● Gene mutations ○ Problems with DNA replication (codon insertion/deletion) ○ Problems with nucleotide sequence of genes ○ DNA damage ● Cell mutations that aren’t dividing aren’t much of a problem ○ No replication changed to replication ● Stem cells still have the ability to divide as needed ○ Damage could be prevalent if division occurs ● How do mutations lead to unrestrained/unrestricted cell proliferation? ○ Control mechanisms maintained to prevent/start division and check stable for replication ○ Cancer cells: mechanisms broken so cells are ALWAYS dividing ■ Disrupt signaling of cell division ○ Cancer cells not completely gone-->can regrow causing a tumour ● Reelin: required to direct migration of stem cells in the brain ● Differential gene expression-->differential protein expression ● kinases ≠ transcription factors ● Different proteins can lead to different shapes, receptors, and functions ● Stem cells must either self-renew or differentiate ○ Can get DNA from any type of cell-->gene just not expressed ● Cells receive signals that tell them what to do ○ survival, growth, division, differentiation, death ■ normal part of development ○ Screwed-up cells are better off dead ■ Path blocked-->problem (CANCER) ○ Signal can be received by the same receptor-->may have different outcomes ○ Cystosolic signaling molecules and effectors are different and so are the transcription factors ● Pathways have branches ○ Must be a branch for two possible outcomes ○ Transcription factors affect/change gene expression ● Apoptosis: programmed cell death Hypothetical (simplified) Transduction Pathway ● MAPK: Mitogen Activated Protein Kinase ● Self Renewal Pathway activated by signal binding event ○ Growth factor signals ○ receptor RTK: Receptor Tyrosine Kinase ○ Kinase domains phosphorylate each other (autophosphorylation) ○ Phosphorylate take from Adenosine Triphosphate (ATP)-->stick onto a protein ■ Dimerization (bring receptors together) of receptor occurs upon signal binding ■ Phosphorylation: Change in the chemistry of a protein ○ Turns on and off the protein ● TFa not phosphorylated-->cannot go into the nucleus ● Phosphorylation causes the chemistry of the molecule to change ○ Activation, deactivation, differential binding characteristics, etc. ■ Proteins structure = function ○ Two types of kinase ■ Serine ■ Threonine ● Signaling pathways can be regulated at every step ● Single cell molecule must have activated the thingamabober and left ■ must dephosphorylate proteins to shut them down ■ IF you have signal cells that phosphorylate whoever dafuq they want-- >nothing good comes out of it ● Transcriptional level ○ Controls level of mRNA ● Translational level ■ Controls how often the mRNA is “read” by the ribosome ● Post-translational level (after protein is made) ■ Phosphorylation/Dephosphorylation ■ Proteolysis (dismantling protein) ■ Endocystosis (remove cell surface proteins/receptors) ● G Protein: peripheral membrane proteins ■ Activated by signal receptor-->trigger key step in signal transduction ■ Production of messenger inside the cell ● Link receipt of extracellular signal to production of intracellular signal ■ Bind GTP and GDP ■ GTP binds to a protein-->addition of negative chargers alter protein’s shape ● Protein Kinases: enzymes that activate/inactivate other proteins by adding phosphate group to them ○ Second messengers aren’t restricted to a single role or cell type ■ Can initiate diff events in diff cell types ○ Common for 1+ second messenger to be involved in triggering cell’s response to same signal ● Phosphorylation Cascade ○ 1. Hormone binds to RTK (receptor tyrosine kinases) ○ 2. Protein forms a dimer ■ REceptor has binding site for a phosphate group from ATP inside the cell ■ Phosphorylated-->RTK becomes active enzyme ○ 3. Proteins in the cell form a bridge between activated RTK and peripheral membrane protein-->Ras, functions like G protein ■ Formation of RTK bridge activates Ras ● Exchanges GDP for GTP ○ 4. Ras activated-->triggers phosphorylation and activation of another protein ○ Phosphorylated protein catalyzes phos. of other proteins-->phos. more proteins ○ Second messengers of protein phosphorylation events may: ■ 1. Change which genes are expressed in the cell ■ Activate/deactivate particular target protein that already exists in the cell ○ Hormone receptor building occurs-->concentration of cGMP rises in cells ● positive feedback loop: expression of protein that activates pathway ● negative feedback: expression of protein that shuts down pathway ● Signal deactivation ○ Presence of second messengers in cystosol short lived ○ Second messengers cleared from cytosol-->response stops ○ Hormone stimulation from RTK ends-->phosphatases can dephosphorylate enough components of phos. cascade so response begins to slow ● Signal transduction systems trigger rapid response and can be shut down quickly ○ Sensitive to small changes in concentration of hormones or number and activity of signal receptors ● Signal transduction pathways form a network ○ IMPORTANT: allows cells to respond to many extracellular signals in an integrated way ○ diverse signals allow them to cross-talk: interactions between signaling pathways ■ Elements or products from one pathway may inhibit steps in a diff. pathway-->reduces cell’s response even though appropo signal is present ○ Response from one pathway may stimulate greater response by a protein in diff. pathway-->increases cell’s response to other signal ● Kinases aren’t transcription factors ● All somatic cells have the same DNA but express different genes!!! ● ID genes received: before skin signal ● Ways to control activity and protein levels ○ Transcriptional level: control levels of mRNA ○ Translational level: control how often mRNA is read by ribosomes ○ Post-translational level ■ phosphorylation/dephosphorylation ■ proteolysis (dismantles proteins) ■ endocytosis (remove cell surface proteins/receptors ● ubiquitin-mediated proteolysis: ubiquitin tagged to protein for destruction ○ proteasome takes proteins-->cuts it up-->recycles ubiquitin for later use ● Cancer cells: lolno fuq da signals i do wat i want we take pride to divide ● CELL CYCLE ● G1: Growth phase-->duplicates nucleotides and makes sure enough are present ● S: DNA replication-->screwed up = DEAD ● M: chromosome segregation ● DNA REPLICATION + CHROMOSOME SEGREGATION とても IMPORTANTE Cell Cycle ● E2F activated (Rb go byebye)-->cells go to cell cycle ○ Rb suppresses it and acts as tumour suppressor ● Cyclin: gas pedal for CDK (Cyclin Dependent Kinase) ● CDK: master cell cycle regulator ● CDK bound to cyclin and phosphorylated-->inactive ● Binds to Rb and gives up a phosphate ● E2F free ● After G1 checkpoint: PAST THE POINT OF NO RETURN ● S phase: cyclins targeted to go through ubiquitin-mediated proteolysis ● Phosphate removed from CDK cyclin-->ACTIVE ● p53: stops cell from dividing via signals and tells cells there’s damage ○ can turn on CDKI ● Damage is too much: p53 acts in apoptosis ○ CDk-cyclin inhibits Rb (Rb inhibits E2F) ○ No Rb = E2F FREEEEEEEEEEE ● Proto-oncogenes: gas pedal for the cell cycle Genetics ● Genotype: organisms DNA sequence ● Phenotype: observable characteristics of an organism ● Homozygous: same alleles ● Heterozygous: alleles different ● Recessive: “to recede or become hidden” (modern day: loss of function mutation)
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