【正文】 mosomal translocation t(14。 or 39。 DFF45), causes the release of the endonuclease, which travels to the nucleus to fragment DNA. Cleavage of cytoskeletal proteins such as actin, plectin, Rho kinase 1 (ROCK1) and gelsolin leads to cell fragmentation, blebbing and the formation of apoptotic bodies. After exposure of 39。executioner39。 and inhibitors of apoptosis proteins (IAPs) bind to and inhibit caspases. FLIPL and FLIPS refer to long and short forms of FLIP, respectively. Mitochondria amp。 of the apoptotic signal. Activation of mitochondria is mediated by the BCL2 family member BID. BID is cleaved by active caspase8 and translocates to the mitochondria. The two main apoptic signalling pathway Apoptosis can be initiated by two alternative pathways: either through death receptors on the cell surface (extrinsic pathway) or through mitochondria (intrinsic pathway). In both pathways, induction of apoptosis leads to activation of an initiator caspase: caspase8 and possibly caspase10 for the extrinsic pathway。. In both pathways, cysteine aspartylspecific proteases (caspases) are activated that cleave cellular substrates, and this leads to the biochemical and morphological changes that are characteristic of apoptosis. ? Death receptors are members of the tumournecrosis factor (TNF) receptor superfamily and prise a subfamily that is characterized by an intracellular domain — the death domain. ? Death receptors are activated by their natural ligands, the TNF family. When ligands bind to their respective death receptors — such as CD95, TRAILR1 (TNFrelated apoptosisinducing ligandR1) or TRAILR2 — the death domains attract the intracellular adaptor protein FADD (Fasassociated death domain protein, also known as MORT1), which, in turn, recruits the inactive proforms of certain members of the caspase protease family. ? The caspases that are recruited to this deathinducing signalling plex (DISC) — caspase8 and caspase10 — function as 39。 Cancer ?? ??????? Initiation of apoptosis ? In principle, there are two alternative pathways that initiate apoptosis: one is mediated by death receptors on the cell surface — sometimes referred to as the 39。extrinsic pathway39。initiator39。 and caspase9, which is activated at the apoptosome, for the intrinsic pathway. The initiator caspases then activate executioner caspases. Active executioner caspases cleave the death substrates, which eventually results in apoptosis. There is crosstalk between these two pathways. For example, cleavage of the BCL2family member BID by caspase8 activates the mitochondrial pathway after apoptosis induction through death receptors, and can be used to amplify the apoptotic signal. Death receptos and ligands Ligands are shown at the top, receptors at the bottom. Death receptors and death ligands are grouped in a box. DcR3 (decoy receptor 3) acts as a decoy receptor for CD95L (dotted line). The other molecules outside the box can bind to death receptors or ligands as indicated, but have not been shown to transmit an apoptotic signal. The death domain is shown as a pink box. Apoptosis signalling through death receptors Binding of death ligands (CD95L is used here as an example) to their receptor leads to the formation of the deathinducing signalling plex (DISC). In the DISC, the initiator procaspase8 is recruited by FADD (FASassociated death domain protein) and is activated by autocatalytic cleavage. Deathreceptormediated apoptosis can be inhibited at several levels by antiapoptotic proteins: CD95L can be prevented from binding to CD95 by soluble 39。 the BCL2 family ? Death initiated at the mitochondrial level is regulated by the members of the BCL2 family. BCL2 family members can be divided into antiapoptotic (BCL2, BCLXL, BCLw, MCL1, A1/BFL1, BOO/DIVA, NR13) and proapoptotic proteins (BAX, BAK, BOK/MTD, BCLXS, BID, BAD, BIK/NBK, BLK, HRK/DP5, BIM/BOD, NIP3, NIX, NOXA, PUMA, BMF). Most antiapoptotic members contain the BCL2 homology (BH) domains 1, 2 and 4, whereas the BH3 domain seems to be crucial for apoptosis induction. The proapoptotic members can be subdivided into the BAX subfamily (BAX, BAK, BOK) and the BH3only proteins (for example, BID, BAD and BIM). ? After activation by an apoptotic stimulus, mitochondria release cytochrome c, AIF (apoptosis inducing factor) and other apoptogenic factors from the intermembrane space to the cytosol. Conitantly, the mitochondrial transmembrane potential drops. According to one model, mitochondrial membrane permeabilization involves the permeability transition pore plex (PTPC), a multiprotein plex that consists of the adenine nucleotide translocator (ANT) of the inner membrane, the voltagedependent anion channel of the outer membrane and various other proteins. BCL2 proteins might interact with the PTPC and regulate its permeability. ? According to another model, BH3only proteins serve as 39。 caspases, mainly caspase3, caspase6 and caspase7. The active executioner caspases then cleave each other and, in this way, an amplifying proteolytic cascade of caspase activation is started. ? Eventually, the active executioner caspases cleave cellular substrates — the 39。eat me39。apoptoticlike39。18), which couples the BCL2 gene to the immunoglobulin heavy chain locus, leading to enhanced BCL2 expression. BCL2 cooperates with the oncoprotein cMYC or, in acute promyelocytic leukaemia, the promyelocytic leukaemia–retinoicacidreceptor (PML–RAR ) fusion protein, thereby contributing to tumorigenesis. Some studies have shown a correlation between high levels of BCL2 expression and the severity of malignancy of human tumours. Moreover, it has been shown in in vitro and in vivo models that BCL2 expression confers resistance to many kinds of chemotherapeutic dru