IntrinsicExtrinsicPathwaysofApoptosis.pptx

MEKANISME APOPTOSIS

1. The Mechanisms of Apoptosis Assistant Prof. Dr. Nibras Saleam Al- Ammar PhD in Clinical Immunology Pathology Dep. Dr. Nibras March 2016

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3. Causes of Apoptosis  Apoptosis occurs in many normal situations & serves to eliminate harmful cells that out-lived their usefulness.  It also occurs as a pathologic event when cells are damaged beyond repair. Dr. Nibras March 2016

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5. Pathological causes of Apoptosis Dr. Nibras March 2016

6. Mechanisms of Apoptosis  Apoptosis results from the activation of enzymes called caspases (cysteine proteases that cleave proteins after aspartic residues).  Activation of caspases depends on a finally tuned balanced between production of pro- & anti-apoptotic proteins. Dr. Nibras March 2016

7. There are two main apoptotic pathways: Dr. Nibras March 2016

8. The Mitochondrial (Intrinsic) Pathway  Mitochondria contain cytochrome c & other proteins that neutralize endogenous inhibitors of apoptosis.  The choice between cell survival & death is determined by the permeability of mitochondria , which is controlled by a family of more than 20 proteins (Bcl-2 family). Dr. Nibras March 2016

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11. The BH3 proteins: also Inhibit the anti-apoptotic molecules (Bcl-2 & Bcl-xL ) . Dr. Nibras March 2016

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14.  Cytochrome c & some cofactors, activate caspase-9.  Other proteins that leak out of mitochondria block the activities of caspase antagonists (that function as physiological inhibitors of apoptosis).  The net result is the activation of the caspase cascade , leading to the nuclear fragmentation. Dr. Nibras March 2016

15.  Conversely, if cells are exposed to growth factors & other survival signals, they synthesize anti-apoptotic proteins (Bcl-2 & Bcl-x L ) . These proteins antagonize Bax & Bak , and thus limit the escape of the mitochondrial pro-apoptotic proteins. Dr. Nibras March 2016

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18. The Death Receptor(Extrinsic) Pathway Dr. Nibras March 2016

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23.  FLIP is cellular protein which considered as caspase antagonist.  FLIP block activation of caspases downstream of death receptors.  Some viruses produce homologues of FLIP to keep infected cell alive. Dr. Nibras March 2016

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25. Activation and Function of Caspases  The mitochondrial & death receptor pathways lead to activation of the initiator caspases , caspase-9 & caspase-8, respectively.  Active forms of these enzymes are produced, cleave & activate another series of caspases (the executioner caspase 3). Dr. Nibras March 2016

26.  Activated caspases cleave numerous targets , leading to activation of nucleases that degrade DNA & nucleoproteins.  Caspases also degrade components of nuclear matrix & cytoskeleton, leading to fragmentation of cells. Dr. Nibras March 2016

27. Why we study the Bcl-2 family? ► Proteins of the Bcl-2 family either enhance or suppress programmed cell death & are centrally involved in cancer development & resistance to chemotherapy. ► Understanding protein features that is critical for designing peptide-based cancer therapeutic & diagnostics.

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