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Thread: Apoptosis-Questions...

  1. #1 Apoptosis-Questions... 
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    1.What causes TNF-alpha to bind to TNF-R1? Heat? Damage?

    2.What is the mechansim that kills excess cells during embryonic development?

    3.I know that when the mitochondrial membrane is ruptured, cardiolipin spills out and later there is a caspase release...what exactly happens to form the apoptostome (if I spelled that correctly?) and then what happens after that to lead to cell death?


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  3. #2  
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    really? no answers ppl?


    I'll give this a final bump...


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  4. #3  
    Forum Professor Zwirko's Avatar
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    1. Not sure what you mean by "causes to bind"? I'm assuming you mean what stimulates certain cells to secrete TNF-alpha? In that case, when cells such as macrophages detect foreign antigens or cell damage then they realease TNF-alpha. So yes, heat and damage would do it, as well as infection.


    To be honest, my brain freaks when confronted with some of these complex signalling pathways. For example, TNF-alpha:

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  5. #4  
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    Thanks for the image. It's very helpful. Two more questions..are all of the reactions powered by ATP? What chemical reactions are taking place?
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  6. #5  
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    Dear Gottsy,

    Are you sure that cardiolipin spills out from the mitochondria? I thought it was a lipid present in mitochondrial membranes, and that it had been suggested to promote mitochondrial targeting of tBid (1)...

    However, when the outer mitochondrial membrane (OMM) is ruptured, certain factors do indeed 'escape' from the intermembrane space of the mito to the cytosol. These factors include cytochrome C (normally involved in the electron transport chain, during oxidative phosphorylation); apoptosis inducing factor (AIF); and, Smac/Diablo. The latter serves to antagonise the function of inhibitor of apoptosis (IAP) proteins, which are generally anti-apoptotic [note the dual character of XIAP - ref. 2].

    Not all of the reactions that occur during the programme of Apoptosis are powered by ATP, but - for example - activation of Apaf-1 involves hydrolysis of its bound dATP to dADP. The chemical reactions that take place are diverse - phosphorylation reactions are prominent during the cellular signalling pathways upstream of mitochondrial outer membrane permeabilisation (MOMP); effectively during the stages when the cell is deciding whether or not to die... Post-MOMP, the reactions are largely proteolytic cleavage resctions, of the caspase cascade - when caspases cleave other caspases in succession.

    It might be easier to think of programmed cell death in terms of a linear series of events. Some of the basics are given in this here http://219.221.200.61/ywwy/zbsw(E)/pic/ech13-17.jpg diagram

    Briefly ~

    Extrinsic Pathway

    Homotrimeric death ligand (e.g. on a killer lymphocyte) binds homotrimeric death receptor on the target cell > adaptor proteins recruited to intracellular tails of death receptors > recruitment of pro-caspase 8/10 molecules to adaptors > cleavage and activation of pro-caspase 8/10 > cleave downstream executioner caspases > active caspases cleave essential cellular proteins, for example the lamins that make up the nuclear lamina > nuclear collapse, and other apoptotic phenotypes > cell death.

    Intrinsic Pathway

    Receipt of death signal (e.g. irreparable DNA damage) > activation of pro-apoptotic members of the Bcl-2 protein family > activation of Bax/Bak on mito > MOMP > release of cyt C (etc) > activation of Apaf-1 into heptameric apoptosome > recruitment of pro-caspase 9 > cleavage and activation of pro-caspase 9 > cleavage of downstream executioner caspases > cell death.

    This account can be found in any decent molecular cell biology undergraduate text. E.g. Alberts' 'Molecular Biology of the Cell' - 5th Ed. = Bible.

    1. Lutter et al (2000) Cardiolipin provides specificity for targeting of tBid to mitochondria. Nature Cell Biology
    2. Owens et al (2009) A role for X-linked inhibitor of apoptosis protein upstream of mitochondrial permeabilization. The Journal of biological chemistry 8)

    Hope this helps,

    Tridimity.
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  7. #6  
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    Good to hear from you, my friend. :P :wink:


    To answer your question, no I've discovered it isn't cardiolipin itself that leaves.

    From Wiki:


    A cardiolipin-specific oxygenase produces CL hydroperoxides which can result in the conformation change of the lipid. The oxidized CL then transfers from the inner membrane to the outer membrane, and then helps to form a permeable pore which releases cyt c.
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