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Intrinsic pathway

As its name suggests, the intrinsic pathway is initiated from within the cell (Figure 2.3). This is usually in response to cellular signals resulting from DNA damage, a defective cell cycle, detachment from the extracellular matrix, hypoxia, loss of cell survival factors, or other types of severe cell stress. This pathway involves the release of pro-apoptotic proteins that activate caspase enzymes from the mitochondria. This process ultimately triggers apoptosis.2,17-19

The intrinsic apoptosis pathway.

Click here to view a PDF of this image. Figure 2.3. Elements of the intrinsic apoptotic pathway.
Adapted from Ashkenazi, 2002.1 Reproduced with permission from Nat Rev Cancer.

The intrinsic apoptotic pathway hinges on the balance of activity between pro- and anti-apoptotic members of the Bcl-2 superfamily of proteins (Table 2.1 and Figure 2.4), which act to regulate the permeability of the mitochondrial membrane.17

Table 2.1. Pro- and anti-apoptotic members of the Bcl-2 superfamily of proteins

BCL-2 Superfamily

Click here to view a PDF of this image.
Adapted from Mayer and Oberbauer, 2003.20 Reproduced with permission from News Phys Sci.

Bcl-2 Superfamily

Click here to view a PDF of this image. Figure 2.4. The role of Bcl-2 proteins in cell survival and apoptosis.
Adapted from Ashkenazi, 2002.1 Reproduced with permission from Nat Rev Cancer.

Members of the Bcl-2 family contain signature domains of homology called Bcl-2 homology (BH) domains (termed BH1, BH2, BH3, and BH4).14 Pro-apoptotic Bcl-2 proteins are divided into 2 subgroups based on the number of BH domains they contain. There are those with several BH domains (eg, Bax and Bak), and then there are those that only have the BH3 domain, such as Bid, Bad, Bim, Bmf, PUMA, and NOXA.14 BH3-only proteins activate the multi-BH domain pro-apoptotic proteins Bax and/or Bak, which then allow for permeabilization of the mitochondrial membrane.14 The anti-apoptotic Bcl-2 proteins Bcl-2 and Bcl-XL act to prevent permeabilization of the outer mitochondrial membrane by inhibiting the action of the pro-apoptotic Bcl-2 proteins Bax and/or Bak (Figure 2.4).14 Upon membrane permeabilization, cytochrome c and the pro-apoptotic protein SMAC/DIABLO are then able to translocate from the intermembrane space of the mitochondria into the cytosol.14 As part of the intrinsic apoptotic pathway, the SMAC/DIABLO protein released from the mitochondria promotes apoptosis by directly interacting with inhibitors of apoptosis proteins (IAPs) and disrupting their ability to inactivate the caspase enzymes.21,22 This is why the intrinsic pathway is sometimes referred to as the mitochondrial pathway.

Cytochrome c binds the adaptor apoptotic protease activating factor-1 (Apaf-1), forming a large multiprotein structure known as the apoptosome (Figure 2.5). Assembly of the apoptosome is highly regulated and may be driven by nucleotide exchange factors and/or ATPase-activating proteins.13 The primary function of the apoptosome seems to be multimerization and allosteric regulation of the catalytic activity of caspase 9.13 Initiator caspase 9 is recruited into the apoptosome and activated from within the adaptor protein complex, which in turn activates the downstream effector caspases 3, 6, and/or 7.21

The role of BCL2 proteins in cell survival and apoptosis.

Click here to view a PDF of this image. Figure 2.5. Elements assemble to form the apoptosome.

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Caspase cascade

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