Apoptosomes

Apoptosomes: engines for caspase activation.

Adams JM, Cory S.

Source

The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3050, Victoria, Australia. adams@wehi.edu.au

Abstract

"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?

CRBCM today: Further evidence of 2nd law of nature

Further evidences of 2nd law of nature/CRBCM

If you compromise Cell divison, the cell will need to be destroyed
one thing is for sure.  DNA Breakage and mistakes or mismatches lead to cell cycle arrest (First law).  What is interesting is that the second law is very much linked to this. Once the repair occurs, a number of peri microtubular reactions need to occur to relieve that arrest and allow continuation of the mitosis.  This is the connection to the second law.
Also as we are further looking into this matter, we are finding further evidence that there is an intricate connection between Microtubule and Mitochondria.   Even the location of Mitochondria is not random and seems linked to the integrity of the filamentous connection.  We are learning about Nuage and Mitochondrial Cement.  The further we look, the more we can now ascertain the existence of the 2nd law.
We are also learning, that not all the antikinesin are the same.  Some are not as important, affecting peripheral molecules, but some involve the location of the "consensus sequence", and may be more important.

We also are learning that Cyclin ubiquitination and therefore destruction could be exacerbated by perimicrotubular disturbances.  Is this the mechanism of bypassing BCL-2 resistance?  More light is needed.

We will let you know what we find at CRBCM.