37.5:
The Intrinsic Apoptotic Pathway
The intrinsic apoptotic pathway is activated by intracellular death signals, such as oxidative stress and DNA damage.
In mammals, the pathway is regulated by the Bcl-2 family of proteins, which has both pro- and anti-apoptotic family members.
Proapoptotic proteins include BH3-only proteins, such as Bad and Bim, and effector Bcl-2 family proteins, such as Bax and Bak. Anti-apoptotic proteins include Bcl-XL and Bcl-2 and inhibit Bax and Bak activity.
Death signals activate the BH3-only proteins, which can either inactivate anti-apoptotic proteins or directly bind to effector proteins.
In either case, these effectors oligomerize on the mitochondrial membrane and form pores that release cytochrome c.
Cytochrome c binds to apoptotic protease activating factor-1, Apaf-1, and Apaf-1 monomers then assemble into a heptameric complex, called the apoptosome.
Next, the initiator procaspase-9 binds to the apoptosome and dimerizes, forming caspase-9.
Finally, caspase-9 activates the executioner caspases that cleave cellular proteins, resulting in apoptosis.
37.5:
The Intrinsic Apoptotic Pathway
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits anti-apoptotic proteins Bcl-2, Bcl-XL, and survivin. This whole chain of events eventually leads to apoptosis of the damaged cells.
Cancer and the Intrinsic Apoptotic Pathway
The intrinsic pathway is inhibited during cancer due to mutations in pro-apoptotic and anti-apoptotic proteins. For example, in melanoma, the overexpressed inhibitor of apoptosis proteins or IAPs causes the inactivation of caspase-9, preventing apoptosis. In most cancer cells, Bcl-2, an anti-apoptotic protein first found in follicular lymphoma, is overexpressed.
Several anti-cancer drugs that can activate the intrinsic apoptotic pathway have been developed. For example, molecules such as Nultlin-2 and MI-219 inhibit the binding of MDM2 to p53, thereby preventing the inactivation of p53 and leading to apoptosis of cancerous cells. Some drug molecules, such as SH122, JP1201, and YM155, inhibit IAPs and help activate caspases, thereby initiating apoptosis in cancer cells.