Cell Cycle - Exam 4 PDF

Chapter 17, Part 1 - cell cycle Cell cycle. Division of a hypothetical eukaryotic cell with two chromosomes to illustrate how two genetically identical daughter cells are produced in each cycle. Each of the daughter cells will often continue to divide by going through additional cell cycles. Overv...

Chapter 17, Part 1 - cell cycle Cell cycle. Division of a hypothetical eukaryotic cell with two chromosomes to illustrate how two genetically identical daughter cells are produced in each cycle. Each of the daughter cells will often continue to divide by going through additional cell cycles. Overview of cell cycle Major chromosomal events of the cell cycle occur in S phase, when the chromosomes are duplicated, and M phase, when the duplicated chromosomes are segregated into a pair of daughter nuclei (in mitosis), after which the cell itself divides into two cyctokinesis. Events of eukaryotic cell division Easily visible processes of nuclear division (mitosis) and cell division (cytokinesis) collectively called M phase, typically occupy only a small fraction of the cell cycle. The other much longer part of the cycle is interphase which includes S phase and the gap phase. Four phases- some cases G phase is absent  Group 1 Article 1 Cell cycle control is similar in all eukaryotes Cell-cycle progression can be studied in various ways In this experiment mouse intestinal cells were treated with EdU a thymidine analog that becomes incorporated into the newly synthesized DNA. then the tissue was fixed and labelled with fluorescent dye that binds to EdU showing cells (pink) that were in S phase at the time of treatment. Measuring cell-cycle timing in live cells The method shown here depends on fluorescence proteins that are present only at specific cell cycle stages. Green fluorescence from GFP tagged geminin is seen from early S phase to mid-mitosis. Red from RFP tagged Cdtl is seen from end of mitosis to the end of G1. Analysis of dna content with a flow cytometer A flow cytometer looks at individual cells and measures their fluorescence. If a cell culture is stained with a dye that becomes fluorescent when it binds to dna then the level of fluorescence of a cell indivates the dna content. Cells in G2 and M phase have replicated their DNA, but have not yet divided, so they have double the DNA content indicated by greater fluorescence (peak 2) Cell cycle control system triggers the major events of cell cycle The cell cycle control system governs cell cycle control at three major regulatory transitions: 1) Start, when the cell commits to cell cycle entry and DNA replication 2) The G2/M transition, when the cell triggers mitosis 3) Metaphase to anaphase transition, which triggers sister chromatid separation Cell cycle control depends on cyclically activated cyclin-dependent protein kinases When cyclin forms a complex with Cdk the protein kinase is activated to trigger specific cell cycle events. Without cyclin, Cdk is inactive. Cyclins were originally names because they undergo a cycle of synthesis and degradation in each cell cycle. The levels of the Cdk proteins, by contrast are constant. Cyclical changes in cyclin protein levels result in the cyclic assembly and activation of cyclin -Cdk complexes at specific stages of the cell cycle. Cyclin- Cdk complexes of the cell cycle control system Concentrations of the three major cyclin types oscillate during the cell cycle. A separate regulatory protein complex, the APC/C, initiates the metaphase to anaphase transition. Phosphorylation of Cdk2 (by CAK) at a threonine residue in the T-loop further activates the enzyme by changing the shape of the T-loop, improving the ability of the enzyme to bind its protein substrates. The regulation of Cdk activity by inhibitory phosphorylation The active cyclin cdk complex is off when the kinase Wee1 phosphorylates two closely spaced sites above the active site. Removal of these phosphates by the phosphatase Cdc25 activates the cyclin-cdk complex. For simplicity, only one inhibitory phosphate is shown. Cak adds the activating phosphate. Inhibition of a cyclin cdk complex by a cki (cdk inhibitor protein). Drawing is based on the three-dimensional structure of the human cyclin A-cdk2 complex bound to cki p27 as determined by x-ray crystallography. The p27 binds to both the cyclin and cdk in the complex distorting the active site of the cdk. It also inserts into the Atp-binding site, further inhibiting the enzyme activity. Protein phosphatases reverse the effects of cdks Structure of the phosphatase pp2a, composed of three subunits. Cell cycle control system Hundreds of cdk substrates are phosphorylated in a defined order - Not well understood how the correct order of phosphorylation is achieved. Positive feedback generates the switch like behavior of cell-cycle transitions positive feedback in the activation of M-cdk. Cdk1 associates with m-cyclin as the levels of m-cyclin gradually rise. The resulting m-cdk complex is phosphorylated on an activating site by cdk-activating kinase (cak) and on a pair of inhibitory sites by Wee1 kinase (for simplicity, only one inhibitory phosphate is shown). The resulting inactive m-cdk complex is then activated at the end of G2 by the phosphate cdc25. Cdc25 is further stimulated by active m-cdk resulting in positive feedback. This feedback is enhanced by the ability of m-cdk to inhibit Wee1. the phosphorylation of both cdc25 and wee1 is reversed by the phosphatase pp2a-b55. As described earlier this phosphatase is inactivated by m-cdk proving another mechanism by which m-cdk activates itself. The Anaphase-promoting complex/cyclosome (Apc/c) triggers the metaphase to anaphase transition by marking other proteins for degradation apc/c assembles polyubiquitin chains on the target protein. In this case, m-cyclin. The polyubiquitylated target is then recognized and degraded in a proteasome. The cell-cycle control system G1 phase is a stable state of cdk inactivity Key regulatory event in late m phase is the inactivation of cdks, which resets the cell-cycle control system as the cell prepares to enter a new cell cycle. In most cells this state of cdk inactivity generates a stable g1 gap phase, during which the cell grows and monitors its environment before committing to a new cell cycle. Cell cycle control system functions as a linked series of biochemical switches. Major categories of biochemical tools that regulate the cell cycle Sequential activation of cdks during cell cycle Core of the cell cycle control system consists of a series of cyclin-cdk complex. The activity of each complex is also influenced by various inhibitory mechanisms which provide information about the extracellular environment, dna damage, and spindle assembly. S phase S-cdk initiates dna replication once per cell cycle Chromosome duplication requires duplication of chromatin structure. Cohesins hold sister chromatids together. S-cdk initiates dna replication once per cell cycle New helicases not loaded until after mitosis, so replication can only initiate once per cell. S phase Chromosome duplication requires duplication of chromatin structure Large amounts of histones produced during s-phase Unknown how heterochromatin/euchromatin structure is reproduced. Cohesins hold sister chromatids together Cohesins hold sister chromatids together After dna replication, two sister chromatids are held together along their length by cohesion complexes This siter-chromatid cohesion sets the stage for a successful mitosis b/c it greatly facilitates the attachment of the two sister chromatids to opposite poles of the mitotic spindle.  cohesin complex Mitosis M-cdk and other protein kinases drive entry into mitosis Brief review of mitosis Prophase: chromosomes condense Prometaphase: spindle microtubules attach to chromosomes Metaphse: chromosomes align at cell equator Anaphase: sister chromatids separate Telophase: chromosomes arrive at opposite ends Cytokinesis: division of the cytoplasm, forming 2-cells Mitosis Two major regulatory steps: 1) M-cdk (m-phase cyclin dependent cyclase) and other protein kinase drive entry into mitosis M-cdk induces the assembly of the mitotic spindle. It also triggers chromosome condensation, the large-scale reorganization of the intertwined chromatids into compact, rodlike structures. 2) The apc/c (anaphase promoting complex/cyclosome) triggers the destruction of securin, liberating a protease that cleaves cohesion and thereby initiates separation of the sister chromatids Cohesin helps configure duplicated chromosomes for separation An electron micrograph of a duplicated mitotic chromosome in which condensin is labeled with antibodies attached to tiny gold particles (dark dots), showing that condensin is found mainly in the central core of the chromosome. Condensin is a five-subunit protein complex that resembles the cohesion ring Mechanism by which condensin might generate dna loops, thereby promoting the compaction of a chromosome. Mitotic spindle is a dynamic microtubule-based machine Microtubule instability increases greatly in mitosis. Microtubules-based motor proteins govern spindle assembly and function Bipolar spindle assembly in most animal cells begins with centrosome duplication Activation of the gtpase ran around mitotic chromosomes In metaphase human cell here, ran activity is highest around the chromosomes, between poles of the mitotic spindle Gef bound to chromatin keeps ran in its gtp bound form near chromosomes, influencing microtubule dynamics. Spindle self-organization by motor proteins Microtubules are not only originating at the centrosomes. They nucleate near the chromosomes as well. Kinetochores attach sister chromatids to the spindle Each microtubule is attached to the kinetochore by interactions with multiple copies of the Ndc80 complex. This complex binds to the sides of the microtubule near its plus end, allowing polymerization and depolymerization to occur while the microtubule remains attached to the kinetochore. Bi-orientation is achieved by trial and error When chromosomes are incorretly attached, tension is low and the kinetochore generates an inhibitory signal that loosens the grip of its microtubule attachment site, When bi-orientation occurs, the high tension at the kinetochore shuts off the inhibitory signal, strengthening microtubule attachment. In animal cells, tension not only increases the affinity of the attachment site but also leads to the attachment of additional microtubules to the kinetochore, forming a thick kinetochore fiber. Multiple forces act on chromosomes in the spindle Attachments that ndc80 has with the microtubule are constantly breaking and reforming at new sites, so the kinetochore remains attached to a microtubule even as the microtubule depolymerizes. This acts to pull the chromosome toward the spindle pole. Microtubule flux in the metaphase spindle To observe microtubule flux, a small amount of fluorescent tubulin is injected into the living cells or cell extracts so that individual microtubules form with a small proportion of fluorescent tubulin. Such microtubules have a speckled appearance when viewed by fluorescence microscopy. Movement of individual speckles can be followed by time-lapse video microscopy. Images of the thin vertical boxed region in B taken every 10 secs are aligned here to show that individual speckles move toward the poles at a rate of about 0.75 um/min indicating that the microtubules are moving poleward. Microtubule flux in the metaphase spindle. The length of a kinetochore microtubule does not change significantly during this experiment because new tubulin subunits are added to the microtubule plus at the same rate as tubulin are removed from the miners end. In this way, the entire microtubule is being pulled towards the spindle pole, pulling on the chromosome. Apc/c triggers sister-chromatid separation and the completion of mitosis In the transition from metaphase (A) to anaphase (B), sister chromatids suddenly and synchronously separate and move toward opposite poles of the mitotic spindle Apc/c triggers sister chromatids separation and the completion of mitosis Activation of apc/c by cdc20 leads to the ubiquitylation and destruction of securin, which normally holds separase in an inactive state. The destruction of securin allows separase to cleave Scc1, a subunit of the cohesin complex holding the sister chromatids together. The forces of the mitotic spindle then pull the sister chromatids apart. My doses mitosis unattached chromosomes block sister chromatid separation spindle assembly checkpoint Any kinetochore that is not properly Attached to microtubules sends out a diffusible negative signal that blocks ABC slash C-ctc 20 activation throughout the cell and that blocks the metaphase to anaphase transition. When the last sister commented pair is Properly attached and bi- oriented, this block is removed, allowing sister-chromatid separation to occur. Destruction of securin begins moments after the last sister chromatid pair becomes bi-oriented on the spindle, and anaphase begins about 20 minutes later. Chromosomes segregate in anaphase A and B Mitosis- telophase Segregation chromosomes are packaged in daughter nuclei at telophase Cytokinesis Actin and myosin II in the contractile ring guide the process of the cytokinesis Local activation of rhoA triggers assembly and contraction of the contractile ring Microtubules of the mitotic spindle determine the plane of animal cell division Phragmoplast guides cytokinesis in higher plants Memrance-enclosed organelles must be distributed to daughter cells during cytokinesis  Some cells reposition their spindle to divide asymmetrically Mitosis can occur without cytokinesis Actin and myosin II in the contractile ring guide the process of cytokinesis The contractile ring (A) drawing of the cleavage furrow in a diving cell. Fluorescence micrographs of a dividing slime mold amoeba stained for actin and myosin II Whereas all of the visible myosin II has redistributed to the contractile ring, only some of the actin has done so the rest remains in the cortex of the nascent daughter cells. Local activation of rhoa triggers assembly and contraction of the contractile ring rhoA is a gtpase which is attached to the inner surface of the cell membrane at the future division site, where it promotes actin filament formation, myosin II assembly, and ring contraction. Cytokinesis Microtubules of the mitotic spindle determine the plane of animal cell division This ensures that the cleavage plane is between the two daughter nuclei Cultured human cell at the beginning of cytokinesis showing the locations of the GTPase RhoA and protein called Cyk4 which is one of two subunits of centralspindlin, a protein complex that is concentrated at the overlapping plus ends of antiparallel microtubules. When the same three-dimensional image is viewed in the plane of the contractile ring, show is rhoA iss seen as a ring beneath the cell surface, while the centralspindlin subunit cyk4 is associated with microtubule bundles scattered throughout the equatorial plane of the cell. Centralspindlin interacts with RhoA GEF, Ect2, to activate RhoA at the equatorial cell cortex, halfway between the spindle pole. Not clear how centralspindlin gets to the cortex The phragmoplast guides cytokinesis is higher plants Can’t pull in the rigid cell wall with a cleavage furrow, so build new wall in the middle instead. Vesicles carrying cell wall material ride the remains of the spindle microtubules to the cell equator, fusing to form the cell plate, which becomes the new cell wall. Cytokinesis  Membrane enclosed organelles must be distributed to daughter cells during cytokinesis Mitochondria and chloroplasts divide on their own ER split in two during cytokinesis Golgi split into fragments which are distributed to opposite ends of the spindle, then reassembled to opposite ends of the spindle, then reassembled in the daughter cells Mitosis can occur without cytokinesis Mitosis without cytokinesis in the early Drosophila embryo The first 13 nuclear divisions occur synchronously and without cytoplasmic division to create a large syncytium. Most of the nuclei migrate to the cortex, and the plasma membrane extends inward and pinches off to surround each nucleus to form individual cells in a process called cellularization. It is thought that this is faster than following each round of division with cytokinesis. Fluorescence micrograph of multiple mitotic spindles in a Drosophila embryo before cellularization. The microtubules are stained green and the centrosomes. Note all the nuclei go through the cycle synchronously. The chromosomes are not labeled. They are present in the dark band at the center of each spindle. Cell cycle part 3 Clarification: cytokinesis Actin and myosin II in the contractile ring guide the process of cytokinesis. Local activation of rhoA triggers assembly and contraction of the contractile ring. Fluorescence micrographs of a dividing slime mold amoeba stained for actin and myosin. Whereas all of the visible myosin II has redistributed to the contractile ring, only some of the actin has done so; the rest remains in the cortex of the nascent daughter cells. Local activation of RhoA triggers assembly and contraction of the contractile ring. RhoA is a GTPase which is attached to the inner surface of the cell membrane. Activity of its GEF (Ect2) is localized to the future division site, keeping RhoA active there. In turn, the active RhoA promotes actin filament formation and myosinII assembly, leading to ring formation and ring contraction. How is Ect2 activity localized? Cytokinesis Microtubules of the mitotic spindle determine the plane of animal cell division This ensures that the cleavage plane is between the two daughter nuclei Experimental manipulation of the position of the spindl e changes the location of the cleavage furrow. How does the position of the spindle determine the location of the spindle determine the location of the contractile ring? A protein complex called centralspindlin forms at the antiparallel microtubules at the spindle midzone. Cultured human cell at the beginning of cytokinesis showing the locations of the GTPase RhoA and protein called Cyk4 which is one of the two subunits of centralspindlin protein complex that is concentrated at the overlapping plus ends of antiparallel microtubules. When the same 3D image is viewed in the plane of the contractile ring, RhoA is seen as a ring beneath the cell surface, while the centralspindlin subunit Cyk4 is associated with antiparallel microtubule bundles scattered throughout the equatorial plane of the cell. Centralspindlin interacts with the RhoA GEF, Ect2, to activate RhoA at the equatorial cell cortex, halfway between the spindle pole. Not clear how centralspindlin gets to the cortex. In summary: - There are overlapping antiparallel microtubules at the middle of the mitotic spindle - During anaphase centralspindlin assemebles at the antiparallel microtubules - Centralspindlin works with Ect2 (RhoA GEF) to activate RhoA at the equatorial cortex. - Activated RhoA triggers assembly of the contractile ring. Meiosis Special type of nuclear division that differs from mitosis In animals, occurs in the gonads Meiosis includes two rounds of chromosome segregation and cell division, but only one round of DNA replication Results in four genetically unique daughter cells (gametes) each with just one set of chromosomes. Meiotic cell division - Starting cell is 2n - Produces four daughter cells that are 1n (haploid) - Daughter cells are each genetically unique Mitotic cell division - Starting cell is 2n - Produces two daughter cells that are 2n (diploid) - Daughter cells are genetically identical to each other and to the mother cell. Why meiosis? In each of your body cells, there are 46 pieces of DNA or chromosomes. One set of 23 came from your mother, second set of 23 came from your father. The 46 chromosomes are arranged as 23 pairs, and the cells are described as being “2n”. Gametes (sperm and eggs) are the exception. They contain 23 chromosomes, and are described as being “1n” or just “n” When sperm and egg fuse, they form a single cell (zygote) that now has 23 pairs, or 46 chromosomes. This cell can then develop into a complete human. Meiosis Meiosis includes two rounds of chromosome segregation Meiosis Duplicated homologs pair during meiotic prophase. This does not happen during mitosis. Homolog pairing and crossing over Homolog pairing culminates in the formation of a synaptonemal complex Homolog synapsis and desynapsis during the different stages of prophase I Red arrows point to regions where synapsis is incomplete. Bivalent with three chiasmata resulting from three crossover Synaptonemal complex is no longer present at this stage. The bivalent is held together by chiasmata and sister chromatids held together by cohesion. Comparison of chromosome behavior in meiosis I, meiosis II, and mitosis In meiosis I, the two sister kinetochores are located side-by-side on each homolog and attach to microtubules from the same spindle pole. Meiosis crossing over holds bivalent together, and contributes to genetic variation In humans, bivalents usually have 2 or 3 crossovers Meiosis frequently goes wrong 96 chromatids to segregate!  Meiosis in mammalian females faces an extra challenge: All meiosis in females begin before birth, and is arrested at the diplotene phase of prophase (1 bivalents have formed, synaptonemal complex is gone) Meiosis does not resume until ovulation of that nascent egg. This can be decades after the start of meiosis! Longer the arrest period, the more likely it is that mistakes will occur as meiosis is completed. Meiosis Nondisjunction: when homologs fail to segregate properly. This results in a cell that does not have enough chromosomes, and another tha has too many. In both cases, called aneuploidy. Control of cell division and cell growth In a multicellular organism, organ and body size determined by three fundamental processes: cell growth, cell division and cell survival, these are regulated by three major classes of extracellular signaling molecules: 1) Mitogens stimulate cell division, primarily by triggering a wave of G1/S-cdk activity. 2) Growth factors stimulate cell growth (an increase in cell mass) by promoting synthesis of proteins and other macromolecules and by inhibiting their degradation 3) Survival factors which promote cell survival by suppressing the form of programmed cell death called apoptosis Cells can enter a specialized nondividing state G0 can be temporary or permanent Mitogens stimulate G1-cdk and G1/S -cdk activities DNA damage blocks cell division DNA damage leads to accumulation of active p53 protein which arrests the cell in G1 until the damage is required. Mutations in p53 result in the cell cycle progressing before damage is repaired. As a result, mutations accumulate. P53 mutations are found in at least half of all human cancers. DNA damage blocks cell division What if the DNA damage cannot be repaired? In single celled organisms like yeast, the cell cycle will eventually resume. The cell may not survive with the damage, but there is no harm in trying. In multicellular organisms, unrepaired DNA damage in a cell may be detrimental to the entire organism. To protect the organism, the cell usually goes into permanent arrest or may activate a programmed cell death pathway. Control of cell division and cell growth Many human cells have a built-in limitation on the number of times they can divide This seems to be associated with telomeres. With each cell division, the telomeres are partially lost, unless extended by the enzyme telomerase. The deteriorating telomeres activate the DNA damage response, arresting the cells in G1. Cell proliferation in accompanied by cell growth In animal cells, the occupation of cell surface receptors by growth factors leads to the activation of a complex signaling pathway that results in the activation of the multisubunits protein kinase mTORC1. Cytosolic amino acids also help activate mTORC1. In single celled organisms like yeast, the presence of nutrients is sufficient to stimulate growth. Proliferating cells usually coordinate their growth and division. Coordination between growth and division is required for cells to maintain their size. It is not well understood how growth and division are coordinated. Possible basic mechanisms are shown: Division and growth are not always coordinated: - Skeletal muscle and nerve cells often grow without cell division - Production of large egg cells requires growth without division - The zygote undergoes several rounds of cell division without growth Chapter 18 - Cell death This chapter is about apotosis, a specific kind of programmed cell death. Cells that have been physically damaged or deprived of oxygen Can I as a result. This is called necrosis in other cases, the cell actively destroys itself by activating one of several genetic programs, one of which is apoptosis. this may happen in response to DNA change, viral infection, or as a normal part of the developmental program of an organism. What does apoptosis look like? Normal cell Cell dying by apoptosis. Lysed cell Chromatin is condensed Around margin of nuclues Why apoptosis? cell death apoptosis eliminates unwanted cells apoptosis depends on an intracellular proteolytic Cascade mediated by Caspases activation of cell surface dead receptors initiates the extrinsic pathway of apoptosis the intrinsic pathway of apoptosis depends on proteins released from mitochondria bcl2 proteins are the critical controllers of the intrinsic pathway of apoptosis An inhibitor of apoptosis and IAP and two n t i a p proteins help control caspase activation in the cytosol of some mammalian cells extracellular survival factors inhibit apoptosis in various ways either excessive or insufficient apoptosis can contribute to disease Apoptosis does it depends on an intracellular proteolytic Cascade mediated by caspases Caspases are a group of proteases. They all have a cysteine in their active side and cleave their targets after an aspartate residue. initiator caspases begin the apoptotic program Initiator caspases activate execution caspases. The mature activated caspase then cleaves a variety of cell target proteins, leading to the controlled apoptotic death of the cell. DNA fragmentation during apoptosis CAD= caspase activated DNase Because the DNA cleavage occurs only at accessible sites in Linker regions between nucleosomes, the DNA is cut into fragments of variable size, equivalent to the DNA associated with either one or multiple nucleosomes, producing a ladder pattern upon DNA gel electrophoresis. Extrinsic versus intrinsic pathways To activation Pathways can lead to apoptosis the extrinsic pathway is triggered from outside the cell the intrinsic pathway is triggered from within the cell Activation of cell surface death receptors initiates the extrinsic pathway of apoptosis Trimeric Fas ligands on the surface of a killer lymphocyte bind to trimeric Fas dead receptors on the surface of a Target cell, inducing the target cell to kill itself by undergoing apoptosis by extrinsic pathway It's not clear in this diagram, but the clustering of the Fas dead receptors depends on binding to Fas ligand. Cell death the intrinsic pathway of apoptosis depends on proteins released from mitochondria Cytochrome c is normally a compound of the electron transport chain within the mitochondria. When released into the cytosol it can induce apoptosis. it's not clear why a mitochondrial protein would wind up being a signal for apoptosis. In this experiment mitochondrial protein, cytochrome C, has been fused with GFP. The cells have also been labeled with a red dye that accumulates in the mitochondria the left two panels confirm that the cytochrome GFP Fusion is located in the mitochondria. The panel on the right shows cells 5 hours after being treated with enough UV light to trigger apoptosis via DNA damage. The 7 cells in the lower right corner have a release cytochrome C into the cytosol. The Binding of cytochrome see to the cytosolic adapter protein Apaf1 one induces a conformational change in a path one, triggering the assembly of Apaf1 into a wheel-like heptamer, and exposing a CAspase Recruitment Domain (CARD). But how does cytochrome C get out? In the Apaf1/caspase complex (apoptosome), the initiator caspase-9 dimers become active so they can cleave/activate downstream executioner caspases. Bcl2 Proteins Are the Critical Controllers of the Intrinsic Pathway of Apoptosis BH=Bcl2 Homology domain How pro-apoptotic Bcl2 family effectors induce MOMP and how anti-apoptotic Bcl2 family proteins block it Most of the pro-apoptotic effector Bak is already attached to the outer mitochondrial membrane before the protein is activated. When activated by an apoptotic stimulus, the protein undergoes a conformational change that allows Bak-Bak oligomerization in the outer membrane, somehow allowing mitochondrial contents to flow into the cytosol, triggering apoptosis. The back holy gummers induce m o m p mitochondrial outer membrane permeabilization by creating openings in the outer membrane that allow cytochrome c and other soluble proteins in the intermembrane space to diffuse into the cytosol. The anti-apoptotic Bcl2 family protein BclxL, like Bak, is Normally bound to the outer mitochondrial membrane, where it can interact while it's bh3 binding group Groove to the expected and exposed bh3 domain on activated bak, thereby blocking bak-bak oligomerization, MOMP, and apoptosis. One way BH3- only proteins such as Bad are thought to indirectly induce MOMP and apoptosis is by inhibiting certain anti-apoptotic Bcl2 family proteins such as BclxL (inhibiting an inhibitor). An inhibitor of apoptosis IAP and two anti IAP proteins help control caspase activation in the cytosol of some mammalian cells. IAP were first identified in certain insect viruses which encode IAP proteins to prevent a host cell that is infected by the virus from activating caspase and killing itself off by apoptosis. Mammalian cells make them to avoid accidental apoptosis from background caspase activity. m o m p releases anti IAP proteins, smac and omi, which inhibit the anti-cast-based activity of XIAP, thereby allowing the activation of these cases in the cytosol. Cell death Extracellular survival factors inhibit apoptosis in various ways These are part of the normal social controls that ensure individual sales behave for the good of the whole organism, by surviving when the cells are needed and killing themselves when they are not. In this example., more nerve cells are produced than can be supported by the Limited amount of survival factors produced by the cells in a Target tissue. As a result, some nerve cells receive an insufficient amount of survival factor to avoid apoptosis. This strategy of our production followed by culling during development helps ensure that all the appropriate target cells are contacted by appropriate nerve cells. Two of the various ways that extracellular survival factors can inhibit apoptosis Some survival factors suppress apoptosis by stimulating the transcription of genes that encode anti-apoptotic BCL2 to family proteins such as BCL2 as shown in here or BclxL. Other survival signals activate the serine/threonine protein kinase Akt, which phosphorylates and inactivates the pro apoptotic bh3 only protein bad. When not phosphorylated, bad promotes apoptosis by binding to an inhibitor of an anti-apoptotic BCL to family proteins such as Bcl2 itself. Once phosphorylated, bad dissociates, freeing BCL2 to suppress apoptosis Cell death Healthy neighbors Phagocytose and Digest apoptotic cells Part of the apoptotic pathway leads to the cell tagging itself with “eat me” signals The most important of these signals is the presence of the phospholipid phosphatidylserine, which is normally only present on the inner (cytosolic side) leaflet of the plasma membrane bilayer. Healthy cell Flippase normally acts to move phosphatidylserine from the outer leaflet to the inner leaflet. It is inactivated by an executioner caspase. Scramblase randomly transfers lipids between the inner and outer leaflets. It is activated by caspase. The Inactivation of flippase and the activation of scramblase results in a lot of phosphatidylserine in the outer leaflet, marking the cell for phagocytosis by other cells. Cell dead either excessive or insufficient apoptosis can contribute to disease. During a stroke or heart attack, some cells die by necrosis due to the interruption and blood supply. If blood flow is restored, some surrounding cells in the damaged tissue proceed to die by apoptosis, contributing to tissue loss. Mutations in mice and humans that inactivate the genes for the Fas receptor or ligand prevent the normal deaths of some types of lymphocytes. This can lead to  autoimmune disorders, because some self-reactive lymphocytes fail to be eliminated and react to the individuals own tissues. Defects in normal inhibitory controls on apoptosis are often seen in cancer cells. The p53 gene is mutated in about 50% of all human cancers, so it no longer promotes apoptosis or cell cycle arrest in response to DNA damage. The cells are able to survive and proliferate even when their DNA is damaged. In this way, they progressively accumulate more mutations, some of which make the cancer more malignant. The BH3-mimetic drug Venetoclax specifically inhibits the Bcl2 anti-apoptotic Bcl2 family protein In some cancers they are high levels of antiapoptotic protein expression. in some of those, these are also high levels of pro apoptotic proteins such as Vim. in this way those cells are primed for apoptosis, and are dependent on high antibiotic protein expression to stay alive. For that reason, those cells are especially sensitive to the input of additional Pro apoptotic signals. They undergo apoptosis in response to a dose of Venetoclax that is too low to affect normal cells. In other words the proper those kills cancer cells but not normal cells.