ENVEJECIMIENTO CELULAR: LA TELOMERASA

1. ENVEJECIMIENTO CELULAR: LA TELOMERASA Sin la actividad de la telomerasa las células pierden un poco de ADN de los extremos de los cromosomas (los telómeros) en cada replicación Figure 12-9. At a growing fork, one strand is synthesized from multiple primers. (a) The overall structure of a growing fork. Synthesis of the leading strand, catalyzed by DNA polymerase III, occurs by sequential addition of deoxyribonucleotides in the same direction as movement of the growing fork. (b) Steps in the discontinuous synthesis of the lagging strand. This process requires multiple primers, two DNA polymerases, and ligase, which joins the 3′-hydroxyl end of one (Okazaki) fragment to the 5′-phosphate end of the adjacent fragment. (Fuente: Lodish et al., 2000)

2. HAY QUE DISTINGUIR ENTRE LA MUERTE CELULAR POR LESIÓN (NECROSIS) DE LA MUERTE CELULARPROGRAMADA (APOPTOSIS) Célula normal Célula apoptótica Figure 23-45. Ultrastructural features of cell death by apoptosis. (a) Schematic drawings illustrating the progression of morphologic changes observed in apoptotic cells. Early in apoptosis, dense chromosome condensation occurs along the nuclear periphery. The cell body also shrinks although most organelles remain intact. Later both the nucleus and cytoplasm fragment, forming apoptotic bodies. These are phagocytosed by surrounding cells. (b) Photomicrographs comparing a normal cell (top) and apoptotic cell (bottom). Clearly visible in the latter are dense spheres of compacted chromatin as the nucleus begins to fragment. [Part (a) adapted from J. Kuby, 1997, Immunology, 3d ed., W. H. Freeman & Co., p. 53. Part (b) from M. J. Arends and A. H. Wyllie, 1991, Inter. Rev. Exp. Pathol.32:223.] (Fuente: Lodish et al., 2000)

3. LA REGULACIÓN DE LA MUERTE CELULAR PROGRAMADA DEPENDE DE TRES CLASES DE PROTEÍNAS Figure 23-49. Overview of the apoptotic pathway in C. elegans and vertebrates. Three general types of proteins are critical in this conserved pathway. Regulators either promote or suppress apoptosis; the two regulators shown here, CED-9 and Bcl-2, both function to suppress apoptosis in the presence of trophic factors. Adapters interact with both regulators and effectors; in the absence of trophic factors, they promote activation of effectors. A family of cysteine proteases serve as effector proteins; their activation leads to degradation of various intracellular substrates and eventually cell death. [Adapted from D. L. Vaux and S. J. Korsemeyer, 1999, Cell96:245.] (Fuente: Lodish et al., 2000) Las proteínas reguladoras de la apoptosis están extraordinariamente conservadas evolutivamente

4. LA FALTA DE FACTORES TRÓFICOS PROMUEVE LA ACTIVACIÓN DE LAS CASPASAS Figure 23-50. Current models of the intracellular pathways leading to cell death by apoptosis or to trophic factor–mediated cell survival in mammalian cells. The details of these pathways in any given cell type are not yet known. (a) In the absence of a trophic factor. Bad, a soluble pro-apoptotic protein, binds to the anti-apoptotic proteins Bcl-2 and Bcl-xl, which are inserted into the mitochondrial membrane. Bad binding prevents the anti-apoptotic proteins from interacting with Bax, a membrane-bound pro-apoptotic protein. As a consequence, Bax forms homo-oligomeric channels in the membrane that mediate ion flux. Through an as-yet unknown mechanism, this leads to the release of cytochrome c from the space between the inner and outer mitochondrial membrane. Cytochrome c then binds to the adapter protein Apaf-1, which in turn promotes a caspase cascade leading to cell death.

5. LA PRESENCIA DE FACTORES TRÓFICOS INHIBE LA APOPTOSIS Figure 23-50. (b) In the presence of a trophic factor such as NGF. In some cells, binding of trophic factors stimulates PI-3 kinase activity, leading to activation of the downstream kinase Akt, which phosphorylates Bad. Phosphorylated Bad then forms a complex with the 14 - 3 - 3 protein. With Bad sequestered in the cytosol, the antiapoptotic Bcl-2/Bcl-xl proteins can inhibit the activity of Bax, thereby preventing the release of cytochrome c and activation of the caspase cascade. [Adapted from B. Pettman and C. E. Henderson, 1998, Neuron20:633.] (Fuente: Lodish et al., 2000)