Apoptosis

Caspase-2 is a highly conserved member of the caspase family involved in the initiation and execution of apoptosis. While its function is still poorly understood, caspase-2 is thought to be important for apoptosis in response to DNA damage, bacterial infection, or abnormal mitosis (1). Caspase-2 contains an N-terminal caspase recruitment domain, the large p19 subunit containing the active site, and the small C-terminal p12 subunit (1). In response to various apoptotic signals caspase-2 undergoes dimerization.

Cellular inhibitor of apoptosis protein-1 (cIAP-1) is an anti-apoptotic protein that is able to bind to caspases and inhibit their activity. Additionally cIAP-1 contains a RING domain with E3 ubiquitin ligase activity that is able to mediate the regulation of NF-kB signaling through the ubiquitination and degradation of various substrate proteins. Depending on cellular context, the RING domain of cIAP-1 can either promote or inhibit apoptosis.

Noxa is a BH3-only protein involved in regulating cell death decisions. Noxa is a primary p53-response gene and is upregulated in response to p53 overexpression or DNA damage. Noxa can also be induced by alternative mechanisms including through a hypoxia-response element found in its promoter. Noxa localizes to mitochondria where it binds to Mcl1, an anti-apoptotic Bcl2 family member.

Caspase 6, also known as Apoptotic protease Mch-2, belongs to the peptidase C14A family. It functions as a downstream enzyme in the caspase activation cascade and is responsible for the execution of apoptosis. Its overexpression promotes programmed cell death.

Diseases associated with CASP6 include thoracic cancer and myocardial infarction.  Among its related super-pathways are DR3 Signaling and Apoptosis and the survival FAS signaling cascade.

Cell death via apoptosis is a basic cellular function occurring through the cell death receptor family and their ligands which signal through downstream adaptor molecules and the caspase protease family. Caspases have a precursor form composed of a prodomain, and large and small catalytic subunit, and are activated through a cleavage adjacent to an aspartate to liberate units and allow formation of an a2b2 tetramer. Caspase 3 is a cytoplasmic caspase with two isoforms (one acts as a dominant negative inhibitor), and is involved in the activation cascade for apoptosis execution.

Myc genes (L-Myc, N-Myc and C-Myc) are a family of transcription factors. c-Myc is involved in transcription regulation, apoptosis and cell growth. Mutations in c-Myc have been tied to several cancers.

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Cytochrome C is an electron carrier protein that localizes in mitochondrion intermembrane space and has been identified as one of the key signaling molecules of apoptosis or programmed cell death. Suppression of the anti-apoptotic members or activation of the pro-apoptotic members of the Bcl2 family leads to altered mitochondrial membrane permeability resulting in release of cytochrome c into the cytosol.

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a toxin, named after the plant genus Plumbago from which it was first isolated in 1968 (1). Since its discovery there have been a wide variety of publications describing its effects on fertility, hyperlipedaemia (high cholesterol) and its use as an anti-bacterial. More recently, there have been multiple efforts to synthesise derivatives and analogues of plumbagin in order to increase its potential as an anti-cancer agent.

ATG5 is a member of the ATG family that regulates autophagy, the evolutionary conserved homeostatic response to a diverse variety of self- and foreign-originating cellular stresses. ATG5 is ubiquitously expressed in cells and found co-localized with cytoplasmic non-muscle actin under normal resting conditions, but upon the triggering of apoptosis, ATG5 expression dramatically ramps up, and ATG5 directly conjugates with other related ATG family proteins to form autophagosomes.

Survivin is an anti-apoptotic protein from a large family with related members such as X-linked IAP, cIAP1 and cIAP2, IAP-like protein-2, melanoma IAP, Livin, and NAIP. Survivin regulates fundamental physiological events including the cell cycle, fetal development, and cell migration.