The intrinsic pathway for programmed cell death

• The intrinsic signaling pathway for programmed cell death involves non-receptor–mediated intracellular signals, inducing activities in the mitochondria that initiate apoptosis (Figure 3)⁷
• Stimuli for the intrinsic pathway include viral infections or damage to the cell by toxins, free radicals, or radiation. Damage to the cellular DNA can also induce the activation of the intrinsic pathway for programmed cell death. These stimuli induce changes in the inner mitochondrial membrane that result in the loss of transmembrane potential, causing the release of pro-apoptotic proteins into the cytosol^5,7
• Pro-apoptotic proteins activate caspases that mediate the destruction of the cell through many pathways. These proteins also translocate into the cellular nucleus, inducing DNA fragmentation, a hallmark of apoptosis⁷
• The regulation of pro-apoptotic events in the mitochondria occurs through activity of members of the Bcl-2 family of proteins and the tumor suppressor protein p53. Members of the Bcl-2 family of proteins may be pro- or anti-apoptotic⁷
  • The anti-apoptotic proteins are Bcl-2, Bcl-x, Bcl-x_L, Bcl-X_S, Bcl-w, and BAG. Some of these proteins are currently under investigation as potential targets for anticancer therapy⁷
  • Pro-apoptotic proteins include Bcl-10, Bax, Bak, Bid, Bad, Bim, Bik, and Blk. It has been suggested that upregulation of these proteins or their increased activation may offer an approach for cancer therapy⁷
  • Cellular pathways that modulate the activities of the p53 protein are also currently being evaluated as targets for potential anticancer therapies¹⁰

Figure 3. Elements of the intrinsic apoptotic pathway.⁹

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