It is well established that a principal mechanism of cell death following ionizing radiation damage involves necrosis.6,7 More recently, radiation research has also focused on apopto-sis as an alternative cell death mechanism following ionizing radiation.6,7 Apoptosis is an active, energy-dependent process in which the cell participates in its own destruction (i.e., programmed cell death).28 Apoptosis is characterized morphologically by cell shrinkage, cell membrane blebbing, chro-matin condensation, and finally by fragmentation into apoptotic bodies. The molecular sequence or cascade of apo-ptosis involves the early release of cytochrome C from mitochondria, activation of an apoptotic protease-activating factor (Apaf-1), activation of caspase 9, and subsequent cleavage of downstream (effector) caspases in a self-amplifying cascade. The apoptotic cascade degrades several essential cellular proteins including b-actin, laminin, and polyadenosine 5'-diphosphate-ribosyl polymerase (PARP).29 This cascade is regulated by members of the Bcl-2 family of proteins, which are either antiapoptotic (Bcl-2, Bcl-xL, Bcl-W) or proapoptotic (BAD, Bax, Bak).28,29 Bcl-2 or Bcl-xL proteins bind and inhibit Apaf-1, which prevents the activation of caspases. However, in the presence of excess Bax, Bcl-2 may be displaced from Apaf-1, allowing caspase cleavage and activation.
The effects of ionizing radiation on apoptosis and cell-cycle arrests are interrelated, as evidenced by the central role of p53.30 In addition to the effects of ionizing radiation-induced p53 protein expression on both the G1 arrest and G2 arrest as detailed in the prior section, p53 is also critical in the induction of apoptosis. For example, human tumor cells with certain mutations in the p53 gene are resistant to undergoing apoptosis following ionizing radiation. Another example of this interrelationship of cell-cycle arrest and apo-ptosis following ionizing radiation damage is demonstrated in isogenic human colon cancer cell lines that differ only in their p21 protein status. Wild-type p21 cells undergo a G1 and G2 cell-cycle arrest with enhanced clonogenic survival following ionizing radiation, whereas cells lacking the p21 protein do not undergo these cell-cycle arrests and proceed to apoptosis.
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