Apoptosomes: engines for caspase activation.
Source
The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3050, Victoria, Australia. adams@wehi.edu.auAbstract
"Activation of the caspases that initiate apoptosis typically requires cognate scaffold proteins, including CED-4 in Caenorhabditis elegans, Apaf-1 in mammals and Dark in Drosophila. Each scaffold protein oligomerizes procaspases into a complex called the apoptosome, but the regulation and biological roles of the scaffolds differ. Whereas CED-4 is restrained by the Bcl-2 homologue CED-9, Apaf-1 is inhibited by its WD40 repeat region, until it is activated by cytochrome c, derived from damaged mitochondria. Although Dark also has a WD40 region, its activation does not seem to involve cytochrome c. CED-4 is essential for apoptosis in the worm and Dark for many apoptotic responses in the fly, but the Apaf-1/caspase-9 system probably amplifies rather than initiates the mammalian caspase cascade."(end of abstract)
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This research further confirms the path of the second law driving the forces down the cascade of events
starting with Microfilament/Microtubule disturbance or destruction. The author clearly feels that once the
Apaf-1/Caspase-9 system is initiated, it amplifies its action leading to apoptosis. Mention of the Bcl-2 (or other molecules comparable) is critical because it is the main barrier to full display toward apoptosis. Last point :the Caspases are also a family of enzymes/protein based structure/meaning the potency to achieve Apoptosis varies.
Apaf-1 is Apoptotic Protease-activating Factor-1, a key factor in the cascade to Apoptosis. I should also stress that this factor is more concentrated in liver, spleen, kidney and brain. Tissues where primary tumors are the toughest to treat. Therefore, targeting this enzyme for activation could drive up Apoptotic cascade or cell death.
Of note, people in full inflammatory process with increased TNF have a mitigated result when it comes to Apoptosis because TNF also stimulate NF-kB which has anti-apoptotic trends. Unless it chooses to go down the path of death-domain signaling way (Fas) or stimulate MAPK pathway which is more pro-apoptotic. ARE PEOPLE WITH AUTOIMMUNE DISEASE POOR RESPONDERS TO TAXOL BASED CHEMOTHERAPY BECAUSE OF THIS? SHOULD WE BE TESTING ANA AND LEVEL OF TNF (Tumor Necrosis Factor) TO GAGE RESPONSE TO THERAPY?
