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Fundamentals of Cell Biology Chapter 13: The Birth and Death of Cells Dr. Saeb Aliwaini 1 Cell cycle – How cells make the decision to begin moving through the stages of replication, and why some cells never make this journey – How cells decide to die Dr. Saeb Aliwaini 2 Coordination of cell division • A multicellular organism needs to coordinate cell division across different tissues & organs – critical for normal growth, development & maintenance • coordinate timing of cell division • coordinate rates of cell division • not all cells can have the same cell cycle Frequency of cell division • Frequency of cell division varies by cell type – embryo • cell cycle < 20 minute – skin cells • divide frequently throughout life • 12-24 hours cycle – liver cells • retain ability to divide, but keep it in reserve M metaphase anaphase • divide once every year or two telophase prophase C G – mature nerve cells & muscle cells • do not divide at all after maturity interphase (G , S, G phases) mitosis (M) cytokinesis (C) G • permanently in G0 S 2 1 2 1 New cells arise from parental cells that complete the cell cycle • Key Concepts : – Cells divide by following carefully scripted program of molecular events collectively called the cell cycle. – The cell cycle is subdivided into five phases named G1, S, G2, M, and G0. Cells not actively dividing reside in G1 or G0 phase. – Progression through the cell cycle is under the control of proteins that form checkpoints to monitor whether the proper sequence of events is taking place. Cells halt at these checkpoints until they complete the necessary steps to continue. Dr. Saeb Aliwaini 5 Overview of Cell Cycle Control • Two irreversible points in cell cycle – replication of genetic material – separation of sister chromatids • Checkpoints – process is assessed & possibly halted sister chromatids centromere single-stranded chromosomes double-stranded chromosomes Checkpoint control system • Checkpoints – cell cycle controlled by STOP & GO chemical signals at critical points – signals indicate if key cellular processes have been completed correctly Checkpoint control system • 3 major checkpoints: – G1/S • can DNA synthesis begin? – G2/M • has DNA synthesis been completed correctly? • commitment to mitosis – spindle checkpoint • are all chromosomes attached to spindle? • can sister chromatids separate correctly? G1/S checkpoint • G1/S checkpoint is most critical – primary decision point • “restriction point” – if cell receives “GO” signal, it divides • internal signals: cell growth (size), cell nutrition • external signals: “growth factors” – if cell does not receive signal, it exits cycle & switches to G0 phase • non-dividing, working state G0 phase • G0 phase – non-dividing, differentiated state – most human cells in G0 phase liver cells M Mitosis G2 Gap 2 S Synthesis in G0, but can be “called G1 Gap 1 G0 Resting back” to cell cycle by external cues nerve & muscle cells highly specialized arrested in G0 & can never divide Activation of cell division • How do cells know when to divide? – cell communication signals • chemical signals in cytoplasm give cue • signals usually mean proteins – activators – inhibitors experimental evidence: Can you explain this? “Point of no return” Dr. Saeb Aliwaini 12 The G2/M checkpoint is the trigger for large-scale rearrangement of cellular architecture • MPF Early experiments characterizing the activity of Mitosis Promoting Factor. Dr. Saeb Aliwaini 13 New cells arise from parental cells that complete the cell cycle – The G1/S checkpoint, called the restriction point or start point, is where cells commit to completing cell division. – Proteins called cyclins play an important role in advancing cells through checkpoints. Dr. Saeb Aliwaini 14 Activation of cyclin-CDK complexes begins in G1 phase Figure 13.04: Scientists discovered the first cyclins when they noted that high cyclin levels with the onset of mitosis in embryos. Cyclin levels drop sharply after this. Dr. Saeb Aliwaini 15 Cyclins & Cdks • Interaction of Cdk’s & different cyclins triggers the stages of the cell cycle “Go-ahead” signals • Protein signals that promote cell growth & division – internal signals • “promoting factors” – external signals • “growth factors” • Primary mechanism of control – phosphorylation • kinase enzymes • either activates or inactivates cell signals Cell cycle signals • Cell cycle controls – cyclins inactivated Cdk • regulatory proteins • levels cycle in the cell – Cdk’s • cyclin-dependent kinases • phosphorylates cellular proteins activated Cdk – activates or inactivates proteins – Cdk-cyclin complex • triggers passage through different stages of cell cycle Control by cyclin/CDK complexes Figure 13.05: Distinct cyclin-cdk complexes control progression through cell cycle checkpoints. Dr. Saeb Aliwaini 19 The cell cycle is divided into five phases • “Resting” cells reside in G0 or G1 phase • Several checkpoints define critical decision-making events in the cell cycle Dr. Saeb Aliwaini 20 Figure 13.02: Checkpoints control progression through the cell cycle. Some of the major checkpoints are shown. Dr. Saeb Aliwaini 21 To start • You need signals >>>>> Dr. Saeb Aliwaini 22 Cell cycle step 1: Signal transduction initiates cell cycle progression. Figure 13.06: The family of mitogen activated protein kinases (MAPKs) and their upstream regulatory proteins. Figure 13.07: A simplified MAP kinase signaling pathway. Dr. Saeb Aliwaini 23 Dr. Saeb Aliwaini 24 Cell cycle step 2: Changes in gene expression are required for progression through the restriction point • progression through the restriction point in mammalian cells requires activation of at least two cyclin/CDK complexes: cyclin D1/CDK4 (or CDK6) and cyclin E/CDK2 • expression of most CDKs does not vary much throughout the cycle, but without their corresponding cyclins, they are not functional Dr. Saeb Aliwaini 25 Cell cycle step 3: Pro- and anti-growth signaling networks converge at the G1/S cyclin-CDK complexes • Phosphorylation • Binding by inhibitory kinases • Subcellular location • Protein degradation Figure 13.08: Summary of the cyclin/cdk activation-inactivation cycle. Dr. Saeb Aliwaini 26 • The key function of G1-Cdk complexes in animal cells is to activate a group of gene regulatory factors called the E2F proteins, which bind to specific DNA sequences in the promoters of a wide variety of genes that encode proteins required for S-phase entry, including G1/S-cyclins, S-cyclins, and proteins involved in DNA synthesis and chromosome duplication. • In the absence of mitogenic stimulation, E2F-dependent gene expressionis inhibited by an inter- action between E2F and members of the retinoblastoma protein (Rb) family. Dr. Saeb Aliwaini 27 Cell cycle step 4: Active cyclin/CDKs phosphorylate pocket proteins, which activate E2Fs Figure 13.09: The transcription factor E2F is inactivated by Rb binding. Figure 13.10: Examples of positive (green) and negative (red) feedback loops controlling E2F function. Dr. Saeb Aliwaini 28 Dr. Saeb Aliwaini 29 How E2Fs enhance expression of some genes while suppressing expression of others remains unclear Figure 13.11: A model of how E2F transcription factors can suppress or activate gene transcription. Dr. Saeb Aliwaini 30 Cell cycle step 5: The DNA replication machinery is activated by protein kinases A key player is a large, multiprotein complex called the origin recognition complex (oRc), which binds to replication origins throughout the cell cycle. In late mitosis and early G1, the proteins cdc6 and other proteins bind to the ORC at origins and help load a group of six related proteins called the Mcm proteins. The resulting large complex is the pre-RC, and the origin is now licensed for replication. Figure 13.12: Assembly of the prereplication complex. Dr. Saeb Aliwaini 31 DNA replication occurs in S phase • 3 key steps Figure 13.13: Activation of the replication complex. Dr. Saeb Aliwaini 32 Cell cycle step 6: DNA integrity is ensured by the G1/S, S/G2, and G2/M checkpoints Figure 13.15: Growth arrest induced by Chk1 and Chk2. Figure 13.14: A current model for DNA repair. Dr. Saeb Aliwaini 33 Cell cycle step 7: Cells increase in size during G2 phase Figure 13.17: Wee1 mutation affects cell size. Compared to normal ("wild-type," WT) yeast, Wee1 mutants grow to half normal size before dividing. Dr. Saeb Aliwaini 34 Cell cycle step 8: Cyclin B/CDK1 activation drives cells through the G2/M checkpoint Figure 13.18: A model for cell size control of cell growth in yeast in G2. Dr. Saeb Aliwaini Figure 13.19: A model for how adhesion to ECM promotes cell growth in mammalian cells. 35 Figure 13.20: Phosphorylation of Cdk1 primes it for activation but also keeps it in an inactive state. Dr. Saeb Aliwaini 36 Cell cycle step 9: Chromosome alignment is ensured by the mitotic spindle assembly checkpoint Figure 13.21: A model for anaphase promotion by APC/C. Dr. Saeb Aliwaini 37 Cell cycle step 10: Onset of cytokinesis is timed to begin only after mitosis is complete • Cytokinesis requires the contraction of the contractile ring that lies just beneath the plasma membrane, perpendicular to the long axis of the mitotic spindle. • It is important that the myosin motors in the ring not activate until mitosis, including reconstitution of the nuclear membrane, is complete. Dr. Saeb Aliwaini 38 Multicellular organisms contain a cell selfdestruct program that keeps them healthy • Key Concepts: – Cells die either by traumatic injury (necrosis) or by a self-destruct program called apoptosis. – Apoptosis begins through at least two molecular mechanisms, called intrinsic and extrinsic pathways. – The family of proteins called caspases includes proteases that promote the degradation of organelles and cytosolic proteins during apoptosis. Dr. Saeb Aliwaini 39 Cells die in 2 different ways: necrosis and apoptosis Figure 13.22: Cellular damage can result in necrosis, as organelles swell and the plasma membrane ruptures. Dr. Saeb Aliwaini 40 Apoptosis is a property of all animal cells and some plant cells Dr. Saeb Aliwaini 41 Apotosis is voluntary Figure 13.23: Sections of the interdigital web show cell death (dark-staining nuclei). This cell death has the characteristics of apoptosis. Dr. Saeb Aliwaini 42 Apoptosis is induced via at least 2 different pathways Figure 13.24: Ligation of death receptors causes the recruitment of the adaptor protein FADD to the intracellular region of the death receptor. Figure 13.25: E2F1 lies at the heart of the growth-versus-death decision making system. Dr. Saeb Aliwaini 43 Targets of pro- and anti-apoptotic transcription factors are members of bcl-2 family Figure 13.26: The Bcl-2 family proteins share up to four Bcl-2 homology domains (BH) and can be antiapoptotic or proapoptotic. Figure 13.27: The Bcl-2 family of proteins compete with members of the antiapoptotoic group to access the apoptotic group in an elaborate hierarchy. Dr. Saeb Aliwaini 44 Mitochondrial Outer Membrane Permeabilization (MOMP) Figure 13.28: Signals for the induction of apoptosis trigger changes in the Bcl-2 family proteins, which function to inhibit or promote apoptosis. Activation of caspase 9 by the apoptososme. Insert, three views of apoptosome structure as determined by electron microscopy. Dr. Saeb Aliwaini 45 Apoptosis triggers the activation of special proteases: the caspases Figure 13.29: Different types of vertebrate caspases are shown schematically. Dr. Saeb Aliwaini 46 The final changes • Stereotypical morphological changes take place during apoptosis – karyorrhexis • Apoptotic cells are cleared by phagocytosis Dr. Saeb Aliwaini 47 • The APC/C catalyzesthe ubiquitylation and destruction of two major pro- teins. The first is securln,which normally protects the protein linkages that hold sister chromatid pairs together in early mitosis. Destruction of securin at the metaphase-toanaphasetransition activatesa proteasethat separatesthe sisters and unleashes anaphase.The S- and M-cyclins are the second major targets of the APC/c. Destroying these cyclins inactivatesmost cdks in the cell Dr. Saeb Aliwaini 48