02.21.11 Lecture 14 - The cell cycle and cell death.
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Transcript of 02.21.11 Lecture 14 - The cell cycle and cell death.
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02.21.11Lecture 14 - The cell cycle and cell
death
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The cell cycle: cells duplicate their contents and divide
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The cell cycle may be divided into 4 phases
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The cell cycle triggers essential processes (DNA replication, mitosis)
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Progression of the cell cycle is regulated by feedback from intracellular events
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Cyclin-dependent protein kinases drive progression through the cell cycle
• Cyclin-dependent kinases (Cdks) are inactive unless bound to cyclins
• Active complex phosphorylates downstream targets
• Cyclin helps to direct Cdks to the target proteins
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Cellular levels of (mitotic) M-cyclin rises and falls during the cell cycle
• M-cyclin levels are low during interphase but gradually increases to a peak level during mitosis
• M-cdk activity is, likewise, low in interphase but increases in mitosis
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The abundance of cyclins (and the activity of Cdks) is regulated by protein degradation
• M-cyclin becomes covalently modified by addition of multiple copies of ubiquitin at the end of mitosis
• Ubiqutination is mediated by the anaphase promoting complex (APC)
• Ubiquitination marks cyclins for destruction by large proteolytic machines called proteasome
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Cdks are also regulated by cycles of phosphorylation and dephosphorylation
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Cdk activates itself indirectly via a positive feedback loop
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Distinct cyclins partner with distinct Cdks to trigger different events of the cell cycle
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S-Cdk triggers DNA replication - its destruction ensures this happens once per cell cycle
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Checkpoints ensure the cell cycle proceeds without errors
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Checkpoint: DNA damage arrests the cell cycle in G1
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Checkpoint: spindle assembly
• Mitosis must not complete unless all the chromosomes are attached to the mitotic spindle
• Mitotic checkpoint delays metaphase to anaphase transition until all chromosomes are attached
• Prolonged activation of the checkpoint -->cell death
• Mechanism of many anti-cancer drugs
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Cells can withdraw from the cell cycle and dismantle the regulatory machinery
• G0 is a quiescent state
• Cdks and cyclins disappear
• Some cells enter G0 temporarily and divide infrequenty (I.e. hepatocytes)
• Other differentiated cell types (neurons) spend their life in G0
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Apoptosis: the necessity for cell death in multicellular organisms
• Embryonic morphogenesis
• Killing by immune effector cells
• Wiring of the developing nervous system
• Regulation of cell viability by hormones and growth factors (most cells die if they fail to receive survival signals from other cells)
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Developmentally-regulated apoptosis
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Apoptosis vs. necrosis
Necrotic cell Apoptotic cells
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Necrosis
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Apoptosis
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Apoptosis occurs very quickly and precisely
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Apoptotic cells are phagocytosed by macrophages
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Caspases are specialized proteases that mediate apoptosis
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Apoptosis is mediated by an intracellular proteolytic cascade
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Cell-surface death receptors regulate the extrinsic pathway of apoptosis
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The intrinsic pathway of apoptosis depends on mitochondria
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The Bcl-2 family of proteins regulate the intrinsic pathway of apoptosis
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Animal cells require extracellular signals to divide, grow, and survive
• Mitogens - stimulate cell division by overcoming cell cycle “brake” that leads to G0
• Growth factors - stimulate growth (increased cell size) by promoting synthesis and inhibiting degradition of macromolecules
• Survival factors - suppress apoptosis
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Mitogens stimulate proliferation by inhibiting the Rb protein
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Growth factors increase synthesis & decrease degradation of macromolecules
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Survival factors mediate essential cell death during formation of the nervous
system
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Survival factors suppress apoptosis by regulating Bcl-2 proteins
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Malfunction of apoptosis leads to disease
• Cancer (TNF produced by macrophages activates extrinsic pathway)
• Neurodegenerative diseases
• AIDS (HIV deactivates Bcl-2)
• Ischemic stroke
• Autoimmune disease (lupus)