Apoptosis initiators

BH3 domain) of the BH3-only proteins binds to other Bcl-2 family members thereby influencing their conformation. This interaction facilitates the release of cytochrome C and other mitochondrial proteins from the intermembrane space of mitochondria. Despite much effort the exact biochemical mechanism which governs this release is not yet fully understood. The release of cytochrome C facilitates the formation of the apoptosome, the second platform for apoptosis initiation besides the DISC. At the apoptosome which is also a multi-protein complex the initiator caspase-9 is activated. At this point the two pathways converge. 

Tlie initiator caspases receive proapoptotic signals and initiate the activation of a caspase cascade. Tliey are activated by an interaction with a transmembrane receptor or by cytotoxic influences. A complex is thus formed known as the apoptosome (see 15.4). The effector caspases are activated by an upstream caspase via a cascade mechanism. They are the component that executes apoptosis, initiates degradation of central proteins and directs the cell to death. 

Figure 6.17 The intracellular signaling leading to apoptosis initiated by mitochondrial damage, DNA damage, or stimulation of Fas or TNF-1 receptors. For full explanation see text.

Because each B-cell clone produces antibody to a single epitope on an antigen, an opportunity exists for producing chemically and functionally homogeneous antibody in substantial quantity. However, the short B-cell lifetime that is determined by normal apoptosis initially made this impractical. However, the discovery by Kohler and Milstein that B cells could be fused with immortal myeloma cells to create hybridomas that can be maintained almost indef-... 

Mitochondria and Apoptosis The loss of mitochondrial integrity is a major route initiating apoptosis (see Chapter 18, section V). The intermembrane space contains procaspases —2, —3, and 9, which are proteolytic enzymes that are in the zymogen form (i.e., must be proteolytically cleaved to be active). It also contains apoptosis initiating factor (AIF) and caspase-activated DNAase (CAD). Cytochrome c, which is loosely bound to the outer mitochondrial membrane, may also enter the intermembrane space when the electrochemical potential gradient is lost. The release of cytochrome c and the other proteins into the cytosol initiates apoptosis. 

Modulates cell proliferation, differentiation, matrix synthesis, apoptosis initiates, promotes, and regulates the development, growth, and remodeling of bone and cartilage Induces bone and cartilage formation plays an important role in cardiac morphogenesis... 

Li YQ, Chen P, Haimovitz-Friedman A et al. (2003) Endothelial apoptosis initiates acute blood-brain barrier disruption after ionizing radiation. Cancer Res 63 5950-5956... 

Cell Cycle Control. Figure 3 The DNA damage checkpoint. In response to DNA damage cells activate p53 dependent and independent checkpoint pathways leading to cell cycle arrest at G1/S and G2/M allowing DNA repair. If the cellular damage cannot be repaired, cells can initiate apoptosis. 

In the very early phases of the acute inflammatory response most of the cells invading the damaged area are polymorphonuclear neutrophils, also denoted as PMNs, which serve as initial line of defense and source of proinflammatory cytokines. These cells, which usually live for 4-5 days, circulate in the blood until they are attracted by chemokines into injured tissues. Whereas physical injury does not recruit many neutrophils, infections with bacteria or fungi elicit a striking neutrophil response. The characteristic pus of a bacterial abscess is composed mainly of apoptotic (apoptosis) and necrotic PMNs. Emigration of neutrophils from the blood starts with a process denoted as margination where neutrophils come to lie at the periphery of flowing blood cells and adhere to endothelial cells (Fig. 1). L-Selectin is expressed... 

A proteolytic cascade occurs when one peptidase activates the next in a proteolytic pathway, and this in turn activates the next and so on. This is a mechanism to amplify the initial signal, because one peptidase molecule can activate many zymogen molecules. Examples of proteolytic cascades include blood coagulation, activation of digestive peptidases in the intestine, and apoptosis. 

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