Apoptosis is a form of programmed cell death Apoptosis Necrosis Apoptosis is responsible for the formation of digits in the developing mouse paw. Chapter 18 Apoptotic cells are biochemically recognizable. Apoptosis is a form of programmed cell death * Programmed cell death removes unwanted cells during development. * Apoptotic cells are biochemically recognizable. * In apoptotic cells, phosphatidylserine flips from the inner leaflet to the outer and serves as an “eat me” signal to phagocytic cells. * Apoptosis depends upon an intracellular proteolytic cascade that is mediated by caspases. * The two best understood signaling pathways that can activate a caspase cascade are known as the extrinsic pathway and the intrinsic pathway. * The intrinsic pathway is regulated by a set of pro- and antiapoptotic proteins that are related to Bcl2. * Either excessive or insufficient apoptosis can contribute to disease. Apoptosis depends upon an intracellular proteolytic cascade that is mediated by caspases. Caspase: They have a cysteine in their active site and cleave substrates at specific aspartic acid residues. Figure 18-5a Apoptosis depends upon an intracellular proteolytic cascade that is mediated by caspases. Initiator Executioner Targets Figure 18-5b The intrinsic pathway of apoptosis Figure 18-8 Release of cytochrome c from mitochondria during apoptosis Figure 18-7 The intrinsic pathway of apoptosis Figure 18-8 Pro-apoptotic Bcl2 proteins stimulate the release of mitochondrial intermembrane proteins Figure 18-9, 10 The interplay between the pro- and anti-apoptotic Bcl2 proteins determines the activity of the intrinsic pathway Figure 18-11a Molecular Biology of the Cell (© Garland Science 2008) The interplay between the pro- and anti-apoptotic Bcl2 proteins determines the activity of the intrinsic pathway Figure 18-11b Molecular Biology of the Cell (© Garland Science 2008) Decreased apoptosis can contribute to tumorigenesis Figure 20-14 CANCER * Cancers are monoclonal in origin and multiple mutations are generally required for their progression. * Tumor progression involves successive rounds of random inherited change followed by natural selection. * A small population of cancer stem cells can be responsible for the maintenance of tumors. * Tumor metastasis is a complex, multi-step process. * Cancer-critical genes fall into two major classes: oncogenes and tumor suppressor genes. * Cancer progression typically involves changes in both of these types of genes * The Rb and p53 proteins are two of the most important tumor suppressor gene products for human cancer. Cancers are generally monoclonal in origin Evidence from X-inactivation mosaics that demonstrates the monoclonal origin of cancers. Figure 20-6 Molecular Biology of the Cell (© Garland Science 2008) Cancer incidence increases with age Figure 20-7 Molecular Biology of the Cell (© Garland Science 2008) Tumor progression involves successive rounds of random inherited change followed by natural selection Figure 20-11 Molecular Biology of the Cell (© Garland Science 2008) Oncogene collaboration in mice: Further evidence for the requirement for multiple mutations during tumor formation Figure 20-36 Cancers may arise from cancer stem cells Figure 20-16 Molecular Biology of the Cell (© Garland Science 2008) Tumor metastasis is a complex multi-step process Fig 20-17 An assay used to detect the presence of an oncogene: the loss of contact inhibition in culture Figure 20-29 Molecular Biology of the Cell (© Garland Science 2008) Some of the major pathway relevant to cancer in human cells Figure 20-37 Molecular Biology of the Cell (© Garland Science 2008) Distinct pathways may mediate the disregulation of cell-cycle progression and the disregulation of cell growth in cancer cells Figure 20-39a Molecular Biology of the Cell (© Garland Science 2008) Dominant & recessive mutations that contribute to cancer Figure 20-27 The types of events that can make a proto-oncogene overactive and convert it into an oncogene. Figure 20-33 Molecular Biology of the Cell (© Garland Science 2008) Chronic Myelogenous Leukemia (CML) & the Philadelphia chromosome Figure 20-5 (Hyperactive Abl) Figure 20-51 Targeted therapy: the success of Gleevec Specifically targeting the Abl enzyme Binds to Abl in active site & “locks” the enzyme into an inactive state Figure 20-52 Molecular Biology of the Cell (© Garland Science 2008) Targeted therapy: the success of Gleevec Specifically targeting the Abl enzyme Figure 20-52c Molecular Biology of the Cell (© Garland Science 2008) Multidrug Therapy: Combating Resistance Figure 20-53 Molecular Biology of the Cell (© Garland Science 2008) The genetic mechanisms that cause retinoblastoma Figure 20-30 Molecular Biology of the Cell (© Garland Science 2008) Figure 20-31 Examples of the ways in which the one good copy of a tumor suppressor locus might be lost through change in DNA sequence, The loss of tumor suppression gene function can involve both genetic and epigenetic changes Figure 20-32 A simplified view of the Rb pathway Figure 20-38a The Rb protein inhibits entry into the cell cycle Figure 20-38b,c Molecular Biology of the Cell (© Garland Science 2008) Mechanisms controlling cell-cycle entry and S-phase initiation in animal cells A central role for the Rb protein Figure 17-62 Molecular Biology of the Cell (© Garland Science 2008) Figure 17-62 (part 1 of 3) Molecular Biology of the Cell (© Garland Science 2008) Figure 17-62 (part 2 of 3) Molecular Biology of the Cell (© Garland Science 2008) The inactivation of the Rb protein is needed for the entry into S-phase Figure 17-62 (part 3 of 3) Molecular Biology of the Cell (© Garland Science 2008)