02.17.10Lecture 14 - The cell cycle and cell deathThe cell cycle: cells duplicate their contents and divideThe cell cycle may be divided into 4 phasesThe cell cycle triggers essential processes (DNA replication, mitosis)Progression of the cell cycle is regulated by feedback from intracellular eventsCyclin-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 proteinsCellular 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 mitosisThe 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 proteasomeCdks are also regulated by cycles of phosphorylation and dephosphorylationCdk activates itself indirectly via a positive feedback loopDistinct cyclins partner with distinct Cdks to trigger different events of the cell cycleS-Cdk triggers DNA replication - its destruction ensures this happens once per cell cycleCheckpoints ensure the cell cycle proceeds without errorsCheckpoint: DNA damage arrests the cell cycle in G1Checkpoint: 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 drugsCells 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 G0Apoptosis: 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)Developmentally-regulated apoptosisApoptosis vs. necrosisNecrotic cell Apoptotic cellsNecrosisApoptosisApoptosis occurs very quickly and preciselyApoptotic cells are phagocytosed by macrophagesCaspases are specialized proteases that mediate apoptosis•Apoptosis is mediated by an intracellular proteolytic cascadeCell-surface death receptors regulate the extrinsic pathway of apoptosisThe intrinsic pathway of apoptosis depends on mitochondriaThe Bcl-2 family of proteins regulate the intrinsic pathway of apoptosisAnimal 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 apoptosisMitogens stimulate proliferation by inhibiting the Rb proteinGrowth factors increase synthesis & decrease degradation of macromoleculesSurvival factors mediate essential cell death during formation of the nervous systemSurvival factors suppress apoptosis by regulating Bcl-2 proteinsMalfunction of apoptosis leads to disease• Cancer (TNF produced by macrophages activates extrinsic pathway)• Neurodegenerative diseases• AIDS (HIV deactivates Bcl-2)• Ischemic stroke• Autoimmune disease
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