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What is the difference between intrinsic and extrinsic apoptosis?

What is the difference between intrinsic and extrinsic apoptosis?


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Hello my Professor has been teaching about apoptosis and sometimes makes the distinction between extrinsic and intrinsic. I am not sure if I know for sure what this means. Does this just refer to intrinsic is a cell doing itself while extrinsic refers to Fas ligand? Thanks.


In both pathways 'the cell does itself' the difference is in the reason.

In short: Intrinsic apoptosis is a response to 'internal damage' eg. damaged DNA, chromosom rearrangement, hang ups in division, hypoxia, etc. that the cell senses itself and 'decides to commit suicide'. This is done by the mitochondrial pathway - release of cytochrome C from the mitochondria activates the caspase cascade that results in programmed cell death. This is like "I'm too damaged, I must die".

In the extrinsic pathway as you have mentioned is indeed related to the FAS ligand (and Fas/FasL being the main pathway for apoptosis), but that is not the only external signal as TNF (also known as TNA-alpha) binding to TNF-R1 (tumor necrosis factor receptor 1) may also lead to apoptosis. These pathways are usually activated by the immune system for example in cellular immune response. This is like "You're abnormal / dangerous / infected, you must die".

Both pathways activates the caspase cascade at some point that results in apoptosis. Either way the actual process of apoptosis is carried out by the cell itself in a programmed, regulated manner.

Source: http://en.wikipedia.org/wiki/Apoptosis This papaer offers a great review on the topic, including both pathways: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2117903/

I'd like to quote few important parts to support my answer:

The extrinsic, intrinsic, and granzyme B pathways converge on the same terminal, or execution pathway. This pathway is initiated by the cleavage of caspase-3 and results in DNA fragmentation, degradation of cytoskeletal and nuclear proteins, cross-linking of proteins, formation of apoptotic bodies, expression of ligands for phagocytic cell receptors and finally uptake by phagocytic cells.

(… )

The extrinsic signaling pathways that initiate apoptosis involve transmembrane receptor-mediated interactions. These involve death receptors that are members of the tumor necrosis factor (TNF) receptor gene superfamily

(… )

The intrinsic signaling pathways that initiate apoptosis involve a diverse array of non-receptor-mediated stimuli that produce intracellular signals that act directly on targets within the cell and are mitochondrial-initiated events.


Intrinsic Apoptosis

Intrinsic apoptosis is triggered by mitochondrial outer membrane permeabilization (MOMP), which occurs either in response to pores mediated by BAX and BAK (proapoptotic members of the BCL-2 family) or to mitochondrial permeability transition (MPT) following opening of the permeability transition pore complex ( Green and Kroemer, 2004 Galluzzi et al., 2012 ). MOMP results in the release from the mitochondrial intermembrane space of various cell death modulators such as cytochrome c, apoptosis-inducing factor (AIF), endonuclease G, Smac/DIABLO or Omi/HtrA2 ( Daugas et al., 2000 Li et al., 2001 Suzuki et al., 2001 van Loo et al., 2002 ), as well as cessation of mitochondrial ATP synthesis, inhibition of the respiratory chain and increased reactive oxygen species (ROS) production ( Galluzzi et al., 2012 ). Intrinsic apoptosis is further subdivided into caspase-dependent and caspase-independent forms ( Galluzzi et al., 2012 ). Cytochrome c, along with Apaf-1 and dATP, form the “apoptosome” – a multiprotein complex that activates caspase-9 to initiate the caspase-3-dependent proteolytic cascade, which is considered a key executioner pathway of apoptotic cell death ( Li et al., 1997 Galluzzi et al., 2012 ). AIF and endonuclease G act in a caspase-independent manner by translocating to the nucleus and mediating large-scale DNA fragmentation these represent distinct executioner mechanisms of cell death ( Daugas et al., 2000 Li et al., 2001 ).


What is the difference between intrinsic and extrinsic apoptosis? - Biology

I’m going to summarize the finer points of intrinsic and extrinsic apoptosis. As always, if you have comments, concerns, or corrections, please comment below!

Intrinsic and extrinsic apoptosis differ in how they are initiated and how they go about activating executioner caspases (caspase 3 and 6 are the major players). Intrinsic is initiated by lots of things including ER stress, decreased growth factors, and genetic damage, among others. Meanwhile, extrinsic is initiated by binding of Fas-FasL forming a Fas associated death domain (FADD) on the cell undergoing apoptosis.

https://www.easybiologyclass.com/intrinsic-pathway-of-apoptosis-apoptosis-molecular-mechanism-part-1/

Intrinsic apoptosis starts with some mechanism OTHER than Fas-FasL binding, things like DNA damage, ER stress, decreased growth factors, etc. Sensors of apoptosis, the BH3 proteins (Bim, Bid, PUMA, NOXA, etc) are upregulated telling the cell to undergo apoptosis. If the cell has undergone DNA damage, the BH3 protein PUMA (p53 upregulated modulator of apoptosis) may have increased expression levels due to increased p53 levels.

Once the cell has committed (so to speak) to undergo intrinsic apoptosis, the mitochondrial membrane proteins that are anti-apoptotic are replaced with pro-apoptotic proteins (Bcl-2/Bcl-x/Mcl-1 –> Bax/Bak). The way I remember that is the proteins without an “a” are anti-apoptotic, the proteins with an “a” are pro-apoptotic. Bax and Bak allow the mitochondria to leak proteins, including cytochrome C. Cytochrome C binds to APAF-1 (apoptosis-activating factor-1) which also binds to caspase-9, forming the apoptosome. This activates caspase-9 allowing to activation of the executioner caspases and DNAse activity downstream.

There are inhibitors of apoptosis (IAPs- including IAP, IAP1, cIAP2, XIAP, I’m sure there’s more) that are active within the cytosol. When Bak/Bax create pores in the mitochrondrial membrane, Smac/Diablo is released along with cytochrome C. Smac/Diablo function to block IAPs (inhibiting the inhibitors = pro-apoptotic).

Extrinsic apoptosis is initiated by the binding of Fas (CD95) to FasL (but binding to TRAIL and the TNFα receptor TNFR1 can also induce the extrinsic pathway of apoptosis). When any of those receptors are activated they create a FADD (or TRADD)- Fas-associated death domain, where three receptors are brought close together. A FADD/TRADD will bring together pro-caspase 8 molecules close together, which is autocatalytic for cleavage into active caspase 8 (the way I remember that caspase 8 is with extrinsic apoptosis is that eight and extrinsic both start with “e”). Caspase 8 then activates executioner caspases 3 and 6 which leads to apoptosis.

The protein FLIP (aka cFLIP, CFLAR) binds to, but does not activate, pro-caspase 8, making it an anti-apoptotic protein.

There can be cross over between the two pathways. When Bid (BH3 protein) is activated, in Fas signaling induced apoptosis (extrinsic) it can activate the incorporation of Bax/Bak into the mitochondrial membrane and subsequent cytochrome c release (leading to intrinsic apoptosis).


Regulation of Intrinsic and Extrinsic Apoptotic Pathways in Osteosarcoma Cells Following Oleandrin Treatment

Our previous study has reported the anti-tumor effect of oleandrin on osteosarcoma (OS) cells. In the current study, we mainly explored its potential regulation on intrinsic and extrinsic apoptotic pathway in OS cells. Cells apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected using fluorescence staining and flow cytometry. Caspase-3 activity was detected using a commercial kit. The levels of cytoplasmic cytochrome c, mitochondrial cytochrome c, bcl-2, bax, caspase-9, Fas, FasL, caspase-8 and caspase-3 were detected by Western blotting. z-VAD-fmk was applied to block both intrinsic and extrinsic apoptosis pathways, and cells apoptosis was also tested. Furthermore, we used z-LEHD-fmk and Fas blocking antibody to inhibit intrinsic and extrinsic pathways, separately, and the selectivity of oleandrin on these pathways was explored. Results showed that oleandrin induced the apoptosis of OS cells, which was accompanied by an increase in ROS and a decrease in MMP. Furthermore, cytochrome c level was reduced in mitochondria but elevated in the cytoplasm. Caspase-3 activity was enhanced by oleandrin in a concentration- and time-dependent manner. Oleandrin also down-regulated the expression of bcl-2, but up-regulated bax, caspase-9, Fas, FasL, caspase-8 and caspase-3. In addition, the suppression of both apoptotic pathways by z-VAD-fmk greatly reverted the oleandrin-induced apoptosis. Moreover, the suppression of one pathway by a corresponding inhibitor did not affect the regulation of oleandrin on another pathway. Taken together, we concluded that oleandrin induced apoptosis of OS cells via activating both intrinsic and extrinsic apoptotic pathways.

Keywords: apoptosis caspases oleandrin osteosarcoma.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

( a ) DAPI and Hoechst staining of U2OS and SaOS-2 cells treated…

( a ) The vitality of hFOB1.19 cell treated with different concentrations of…

( a ) Intracellular ROS…

( a ) Intracellular ROS level of U2OS and SaOS-2 cells treated with…

( a ) Protein expression…

( a ) Protein expression of cytoplasmic and mitochondrial cytochrome c detected by…

The expression of marker proteins…

The expression of marker proteins (bcl-2, bax, caspase-9, Fas, FasL, caspase-8 and caspase-3)…

( a ) Apoptosis changes…

( a ) Apoptosis changes of cells that pre-treated with z-VAD-fmk followed by…


Ponyboydesigns

Difference Between Extrinsic And Intrinsic Apoptosis. Intrinsic pathway of cell death is triggered when the cell experiences cell stress. Ø killer lymphocytes can induce apoptosis by producing a protein called fas ligand.

Nlrx1 plays a key role in regulating apoptotic cell death and is important in the control of tumorigenesis.conclusion: Difference between apoptosis and necrosis. The mechanisms initiating apoptosis include both intrinsic and extrinsic signals, are complex and there is considerable crosstalk between them. Apoptosis can be initiated through one of two pathways. Click to see full answer.

Intrinsic and Extrinsic Motivation - YouTube from i.ytimg.com In the intrinsic pathway the cell kills itself because it senses cell stress, while in the extrinsic pathway the cell kills itself because of signals from other cells. At least two broad signaling pathways can cause apoptosis. Difference between apoptosis and necrosis. Apoptosis can work mainly by two pathways intrinsic pathway and extrinsic pathway. Nlrx1 regulates the balance between extrinsic and intrinsic apoptosis in cancer cells.significance:

The caspase cascade responsible for executing cell death following cytochrome c release is well described

The extrinsic, intrinsic, and granzyme b pathways converge on the same terminal, or execution pathway. Nlrx1 regulates the balance between extrinsic and intrinsic apoptosis in cancer cells.significance: Ø the fas ligand binds to its receptor called fas on the plasma membrane of the target cell. Difference between extrinsic pathway and intrinsic pathway. Weak external signals may also activate the intrinsic pathway of apoptosis. The intrinsic pathway of apoptosis pathway begins when an injury occurs within the cell and the resulting stress activates the apoptotic pathway. Weak external signals may also activate the intrinsic pathway of apoptosis. Another commonly observed extrinsic pathway of apoptosis in human is by the killer lymphocytes through fas ligand and fas protein by the mechanism given below: A slight mistake during apoptosis results in fused toes or fingers. In the intrinsic pathway the cell kills itself because it senses cell stress, while in the extrinsic pathway the cell kills itself because of signals from other cells. This orally active compound can inhibit tumor growth or metastasis in tumor models without inducing any clinical sign of toxicity. Nlrx1 plays a key role in regulating apoptotic cell death and is important in the control of tumorigenesis.conclusion: Apoptosis can be triggered in a cell through either the extrinsic pathway or the intrinsic pathway.

Another commonly observed extrinsic pathway of apoptosis in human is by the killer lymphocytes through fas ligand and fas protein by the mechanism given below: The intrinsic pathway involves mitochondria whereas the extrinsic pathway relies on external tnggers 0 c. In the intrinsic pathway the cell kills itself because it senses cell stress, while in the extrinsic pathway the cell kills itself because of signals from other cells. The extrinsic, intrinsic, and granzyme b pathways converge on the same terminal, or execution pathway. Weak external signals may also activate the intrinsic pathway of apoptosis.

Intrinsic And Extrinsic Aging [What's The Difference . from i.pinimg.com Here we demonstrate several unique functions for each of these caspases. The mechanisms initiating apoptosis include both intrinsic and extrinsic signals, are complex and there is considerable crosstalk between them. The difference between intrinsic and extrinsic pathways in blood clotting depends on their initiation factors The intrinsic pathway involves mitochondria whereas the extrinsic pathway relies on external tnggers 0 c. Weak external signals may also activate the intrinsic pathway of apoptosis.

The extrinsic pathway involves mitochondria whereas the intrinsic pathway relies on external triggers o b.

Nlrx1 plays a key role in regulating apoptotic cell death and is important in the control of tumorigenesis.conclusion: The caspase cascade responsible for executing cell death following cytochrome c release is well described At least two broad signaling pathways can cause apoptosis. Here we demonstrate several unique functions for each of these caspases. The extrinsic pathway involves mitochondria whereas the intrinsic pathway relies on external triggers o b. This orally active compound can inhibit tumor growth or metastasis in tumor models without inducing any clinical sign of toxicity. Apoptosis can be triggered in a cell through either the extrinsic pathway or the intrinsic pathway. Weak external signals may also activate the intrinsic pathway of apoptosis. The extrinsic, intrinsic, and granzyme b pathways converge on the same terminal, or execution pathway. The intrinsic pathway starts as a result of an injury inside the cell. Apoptosis can work mainly by two pathways intrinsic pathway and extrinsic pathway. Intrinsic pathway of cell death is triggered when the cell experiences cell stress. Difference between extrinsic pathway and intrinsic pathway.

The intrinsic pathway starts when there is a trauma in blood or when blood is exposed to a collagen. A slight mistake during apoptosis results in fused toes or fingers. The extrinsic, intrinsic, and granzyme b pathways converge on the same terminal, or execution pathway. Apoptosis can be initiated through one of two pathways. Intrinsic (mitochondrial pathway) and extrinsic (death receptor pathway) as shown in figure 01.

Difference between intrinsic and extrinsic. Difference . from image.slidesharecdn.com The extrinsic pathway involves mitochondria whereas the intrinsic pathway relies on external triggers o b. Intrinsic (mitochondrial pathway) and extrinsic (death receptor pathway) as shown in figure 01. The extrinsic pathway starts on the outer section of the cell when circumstances in the extracellular environment decide that the cell is supposed to die. Multicellular organisms have two distinct apoptosis pathways Intrinsic pathway of cell death is triggered when the cell experiences cell stress.

The caspase cascade responsible for executing cell death following cytochrome c release is well described

Extrinsic pathway is initiated after the release of a tissue factor to the blood due to a trauma to the vascular wall or surrounding tissues while intrinsic pathway is initiated when collagen contacts with the blood due to blood trauma. Difference between apoptosis and necrosis. The extrinsic pathway of apoptosis begins outside a cell, when conditions in the extracellular environment determine that a cell must die. The extrinsic pathway is initiated through the stimulation of the transmembrane death receptors, such as the fas receptors, located on the cell membrane. Another commonly observed extrinsic pathway of apoptosis in human is by the killer lymphocytes through fas ligand and fas protein by the mechanism given below: Nlrx1 regulates the balance between extrinsic and intrinsic apoptosis in cancer cells.significance: The intrinsic pathway starts as a result of an injury inside the cell. In contrast, the intrinsic pathway is initiated through the release of signal factors by. The intrinsic pathway mainly triggers apoptosis in response to an internal. The intrinsic pathway involves mitochondria whereas the extrinsic pathway relies on external tnggers 0 c. Apoptosis can be initiated through one of two pathways. Weak external signals may also activate the intrinsic pathway of apoptosis. The extrinsic, intrinsic, and granzyme b pathways converge on the same terminal, or execution pathway.

Intrinsic pathway of cell death is triggered when the cell experiences cell stress. Intrinsic is initiated by lots of things including er stress, decreased growth factors, and genetic damage, among others. The intrinsic pathway of apoptosis pathway begins when an injury occurs within the cell and the resulting stress activates the apoptotic pathway. Multicellular organisms have two distinct apoptosis pathways Ø killer lymphocytes can induce apoptosis by producing a protein called fas ligand.

Apoptosis can work mainly by two pathways intrinsic pathway and extrinsic pathway. Difference between apoptosis and necrosis. At least two broad signaling pathways can cause apoptosis. The discrepancies in data may be explained by the relative contribution of the extrinsic versus the intrinsic pathway depending on the cytotoxic drug, dose or kinetics or on the differences. The caspase cascade responsible for executing cell death following cytochrome c release is well described

Source: static.bio-rad-antibodies.com

The difference between intrinsic and extrinsic pathways in blood clotting depends on their initiation factors There is the extrinsic pathway and intrinsic pathway. The caspase cascade responsible for executing cell death following cytochrome c release is well described The extrinsic pathway of apoptosis begins outside a cell, when conditions in the extracellular environment determine that a cell must die. Apoptosis can be initiated through one of two pathways.

There is the extrinsic pathway and intrinsic pathway.

Source: differencebetweenz.com

Intrinsic (mitochondrial pathway) and extrinsic (death receptor pathway) as shown in figure 01.

Source: image.slidesharecdn.com

The intrinsic pathway of apoptosis, also known as the mitochondrial pathway of apoptosis, is initiated following dna damage, activation of p53, triggering a cascade of events leading to mitochondrial.

In the intrinsic pathway the cell kills itself because it senses cell stress, while in the extrinsic pathway the cell kills itself because of signals from other cells.

Source: www.researchgate.net

Weak external signals may also activate the intrinsic pathway of apoptosis.


APOPTOSIS

Apoptosis, or programmed cell death, is a highly regulated process that allows a cell to self-degrade in order for the body to eliminate unwanted or dysfunctional cells. During apoptosis, the genome of the cell will fracture, the cell will shrink and part of the cell will disintegrate into smaller apoptotic bodies. Unlike necrosis, where the cell dies by swelling and bursting its content in the area, which causes an inflammatory response, apoptosis is a very clean and controlled process where the content of the cell is kept strictly within the cell membrane as it is degraded [1]. The apoptotic cell will be phagocytosed by macrophages before the cell’s contents have a chance to leak into the neighbourhood [1]. Therefore, apoptosis can prevent unnecessary inflammatory response.

Apoptosis is essential to embryonic development and the maintenance of homeostasis in multicellular organisms. In humans, for example, the rate of cell growth and cell death is balanced to maintain the weight of the body. During fetal development, cell death helps sculpt body shape, separating digits and making the right neuronal connections. In the immune system, cell death eliminates B cells and T cells that elicit autoimmune response and selects the most efficient lymphocytes to encounter an antigen in the process of affinity maturation.

Apoptosis can be triggered in a cell through either the extrinsic pathway or the intrinsic pathway. The extrinsic pathway is initiated through the stimulation of the transmembrane death receptors, such as the Fas receptors, located on the cell membrane. In contrast, the intrinsic pathway is initiated through the release of signal factors by mitochondria within the cell.


Figure 1. Apoptosis – the programmed death of a cell.

The Extrinsic Pathway: In the extrinsic pathway, signal molecules known as ligands, which are released by other cells, bind to transmembrane death receptors on the target cell to induce apoptosis. For example, the immune system’s natural killer cells possess the Fas ligand (FasL) on their surface [2]. The binding of the FasL to Fas receptors (a death receptor) on the target cell will trigger multiple receptors to aggregate together on the surface of the target cell. The aggregation of these receptors recruits an adaptor protein known as Fas-associated death domain protein (FADD) on the cytoplasmic side of the receptors. FADD, in turn, recruits caspase-8, an initiator protein, to form the death-inducing signal complex (DISC). Through the recruitment of caspase-8 to DISC, caspase-8 will be activated and it is now able to directly activate caspase-3, an effector protein, to initiate degradation of the cell. Active caspase-8 can also cleave BID protein to tBID, which acts as a signal on the membrane of mitochondria to facilitate the release of cytochrome c in the intrinsic pathway [3].

The Intrinsic Pathway: The intrinsic pathway is triggered by cellular stress, specifically mitochondrial stress caused by factors such as DNA damage and heat shock [3]. Upon receiving the stress signal, the proapoptotic proteins in the cytoplasm, BAX and BID, bind to the outer membrane of the mitochondria to signal the release of the internal content. However, the signal of BAX and BID is not enough to trigger a full release. BAK, another proapoptotic protein that resides within the mitochondria, is also needed to fully promote the release of cytochrome c and the intramembrane content from the mitochondria [4]. Following the release, cytochrome c forms a complex in the cytoplasm with adenosine triphosphate (ATP), an energy molecule, and Apaf-1, an enzyme. Following its formation, the complex will activate caspase-9, an initiator protein. In return, the activated caspase-9 works together with the complex of cytochrome c, ATP and Apaf-1 to form an apoptosome, which in turn activates caspase-3, the effector protein that initiates degradation. Besides the release of cytochrome c from the intramembrane space, the intramembrane content released also contains apoptosis inducing factor (AIF) to facilitate DNA fragmentation, and Smac/Diablo proteins to inhibit the inhibitor of apoptosis (IAP) [4].


Figure 2. The intrinsic and extrinsic pathways leading to apoptosis.

Cancer may arise from the dysfunction in the apoptotic pathway. Due to the sensitivity of the intrinsic pathway, tumors arise more often through the intrinsic pathway than the extrinsic pathway [5]. In the intrinsic pathway, a very common cause of tumorgenesis is mutation of the p53 protein [5]. Besides regulating apoptosis, p53 also regulates the check points in the cell cycle, DNA repair, senescence and genomic integrity [6]. Any mutation that causes p53 to lose any of its function will induce tumorgenesis by letting the cell grow indefinitely without any regulation. Another important factor in tumorgenesis is the balance between the proapoptotic and antiapoptotic members of Bcl-2 family. In a tumor cell, a mutation of Bcl-2 gene that results in increased expression will suppress the normal function of the proapoptotic proteins, BAX and BAK [5]. On the other hand, if a mutation on the BAX or BAK genes cause a downregulation of expression then the cell will also lose its ability to regulate apoptosis, again causing tumorgenesis [5].

Human immunodeficiency virus (HIV) contains many gene products that can kill the infected immune cells by activating the apoptotic pathway so that it might weaken the host’s immunity. Mainly, HIV can induce apoptosis through cell fusion (syncytia) or through its gene-encoded products. In preparation for syncytia, HIV will express one of its encoded proteins, Env, on the surface of the infected host cell. Env will bind to CD4 receptors on an uninfected cell and trigger cell fusion [7]. The fused cell will upregulate one of its cell-cycle regulating proteins, cyclin B-CDK1, which leads to the disruption of the cell cycle [7]. The disrupted cell cycle leads to more p53 production and triggers apoptosis through the intrinsic pathway by the upregulation of BAX. Besides syncytia, HIV can induce apoptosis directly through the proteins that its genes encode. For instance, Vpr can induce the intrinsic apoptotic pathway by disrupting the mitochondrial membrane potential and promoting the release of cytochrome C. Tat, on the other hand, promotes apoptosis by downregulating BCL-2 and upregulating caspase [8 7].

The apoptotic pathway is one of the most sophisticated pathways discovered in the cell to date. Its activity is tightly regulated and monitored by the cell. Recent advances and understanding of the apoptotic pathway have led to better and more innovative treatments against cancer and other diseases. However, the detailed mechanism of the apoptotic pathway is still waiting to be elucidated.

1. Raff, Martin. Cell suicide for beginners. Nature 396(1998): 119-122.

2. Csipo, I., Montel, A. H., Hobbs, J. A., Morse, P. A., and Brahmi, Z. Effect of Fas+ and Fas- target cells on the ability of NK cells to repeatedly fragment DNA and trigger lysis via the Fas lytic pathway. Apoptosis 3(1998): 105-114.

3. Adrain, C., Creagh, E. M., and Martin, S. J. Caspase Cascades in Apoptosis. Caspases-their role in cell death and cell survival. Ed. Marek Los and Henning Walczak. Moleculare Biology Intelligence Unit 24. New York: New York, 2002. 41-51.

4. Hague, A., and Paraskeva, C. Apoptosis and disease: a matter of cell fate. Nature Cell Death and Differentiation 3 September 2004: 1-7.

5. Johnstone, R. W., Ruefli, A. A., and Lowe, S. W. Apoptosis: a link between cancer genetics and chemotherapy. Cell 108(2002): 153-164.

6. Schmitt, C. A., Fridman, J. S., Yang, M., Baranow, E., Hoffman, R. M., and Lowe, S. W. Dissecting p53 turmor suppressor functios in vivo. Cancer Cell 1(2002): 289-91.

7. Gougeon, Marie-Lise. Apoptosis as an HIV strategy to escape immune attack. Nature 3(2003): 392-404.


Intrinsic Apoptosis Pathway

The intrinsic apoptosis signaling pathways that initiate apoptosis involve a diverse array of non-receptor-mediated stimuli that produce intracellular signals that act directly on targets within the cell and are mitochondrial-initiated events.

The stimuli that initiate the intrinsic apoptosis signaling pathway produce intracellular signals that may act in either a positive or negative fashion. Negative signals involve the absence of certain growth factors, hormones and cytokines that can lead to failure of suppression of death programs, thereby triggering apoptosis.

In other words, there is the withdrawal of factors, loss of apoptotic suppression, and subsequent activation of apoptosis. Other stimuli that act in a positive fashion include, but are not limited to, radiation, toxins, hypoxia, hyperthermia, viral infections, and free radicals.


Extrinsic Apoptosis Pathway

In molecular biology, the words extrinsic pathway may refer to both the extrinsic pathway of apoptosis and the extrinsic pathway of blood coagulation. Here we mainly talk about the first kind of extrinsic pathway which is extrinsic apoptosis pathway. Extrinsic apoptosis pathway is one of the signal pathways which may trigger the process of programmed cell death namely cell apoptosis.

Overview of Extrinsic Apoptosis Pathway

Apoptosis is known as a physiological process of cell deletion and is also a process of programmed cell death, resulting in morphological change and DNA fragmentation. It is stimulated by external or internal events of cells, one of which is the extrinsic pathway mediated by the death receptor. The death receptors include Fas receptors, tumor necrosis factor (TNF) receptors, and TNF-related apoptosis-inducing ligand (TRAIL) receptors. As a surface receptor, for example, TNF receptor-1 (TNF-R1), it will interact with TNF to induce the recruitment of adaptor proteins such as Fas-associated protein with death domain (FADD) and Tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD), which recruits a series of downstream factors, including Caspase-8, which is a critical mediator of the extrinsic pathway, resulting eventually in cell apoptosis.

Figure 1. An overview of extrinsic apoptosis pathway.

Process and Regulation of Extrinsic Apoptosis Pathway

The extrinsic pathway that initiates apoptosis is triggered by a death ligand binding to a death receptor, such as TNF-α to TNFR1. The TNFR family is a large family consisting of 29 transmembrane receptor proteins, organized in homotrimers and activated by binding of the respective ligand(s). They share similar cysteine-rich extracellular domains and have a cytoplasmic domain of about 80 amino acids called the "death domain" (DD). This death domain plays a critical role in transmitting the death signal from the cell surface to the intracellular signaling pathways. There are 19 members of the TNF ligand family and binding may result in a number of responses, including proliferation, inflammation, and apoptosis, depending on the adaptor proteins associated with the activated receptor.

TNFR may also stimulate pro-inflammatory pathways leading to activation of NFκB, via recruitment of RIP. The death domain kinase RIP is essential for TRAIL-induced IκB kinase (IKK) activation. It has been identified that the binding of TNF-α and TNFR1 activates NFkB pathway, which favored both cell survival and apoptosis, depending on the cell type and biological context.

Besides TNFR1, the Fas and DR4/DR5 also involved the pathway as death receptors and bind CD95 and TRAIL, respectively. All of the ligand binding to receptors will lead, with the help of the adapter proteins (FADD/ TRADD) to recruitment, dimerization, and activation of a caspase cascade and eventually cleavage of both cytoplasmic and nuclear substrates. To date, the best-characterized ligands and corresponding death receptors include CD95/Fas, TNF-α/TNFR1, Apo2L/DR4 and Apo2L/DR5.

Receptor trimerization results in recruitment of several death domains and eventually recruitment and activation of caspase-8 and caspase-10. Active caspase-8 and caspase-10 then either initiate apoptosis directly by cleaving and thereby activating executioner caspase-3/6/7), or activates the intrinsic apoptotic pathway through cleavage of the BID to induce efficient cell death. Immuno-blot analysis also revealed that the caspase-6 inhibitor blocked the cleavage of lamin A/C, whilst the caspase-3/7 inhibitor blocked the cleavage of poly (ADP-ribose) polymerase (PARP). Activation of caspase-8 may be prevented by FLICE inhibitory protein (FLIP).

Taken together, these results suggest that activation of caspases, the subsequent cleavage of lamin A/C and PARP, and the NFkB pathway are involved in the extrinsic pathway of cell apoptosis.

Importance of Extrinsic Apoptosis Pathway

Apoptosis is a process whereby cells undergo programmed death and is a counterbalance to proliferation. It is morphologically distinct from necrosis and involves shrinkage and fragmentation of both the nucleus and the cell without rupture of the cellular membrane. This prevents inflammation of the surrounding tissue. Apoptosis relies on activation of distinct signaling pathways that are often deregulated in cancer. Thus, our ability to exploit these pathways to design more effective and non-toxic therapies for cancer is dependent on our understanding of the biologic mechanisms.


What causes extrinsic apoptosis?

Apoptosis can be triggered in a cell through either the extrinsic pathway or the intrinsic pathway. The extrinsic pathway is initiated through the stimulation of the transmembrane death receptors, such as the Fas receptors, located on the cell membrane. Apoptosis &ndash the programmed death of a cell.

Additionally, what is the difference between intrinsic and extrinsic apoptosis? Apoptosis can be initiated through one of two pathways. In the intrinsic pathway the cell kills itself because it senses cell stress, while in the extrinsic pathway the cell kills itself because of signals from other cells. Weak external signals may also activate the intrinsic pathway of apoptosis.

Similarly, what is extrinsic apoptosis?

Extrinsic Apoptosis Pathway. In molecular biology, the words extrinsic pathway may refer to both the extrinsic pathway of apoptosis and the extrinsic pathway of blood coagulation. Extrinsic apoptosis pathway is one of the signal pathways which may trigger the process of programmed cell death namely cell apoptosis.

Why does apoptosis happen?

Apoptosis is an orderly process in which the cell's contents are packaged into small packets of membrane for &ldquogarbage collection&rdquo by immune cells. Apoptosis removes cells during development, eliminates potentially cancerous and virus-infected cells, and maintains balance in the body.


What is the difference between intrinsic and extrinsic apoptosis? - Biology

Mechanisms of Blood Coagulation

Blood coagulation refers to the process of forming a clot to stop bleeding. Coagulation is a complicated subject and is greatly simplified here for the student's understanding.

To stop bleeding, the body relies on the interaction of three processes:
Primary hemostasis involves the first two processes.
1. Vasoconstriction. Vasoconstriction is the body's first response to injury in the vascular wall. When injury occurs, vessel walls constrict, causing reduced blood flow to the site of injury.
2. Platelet plug. Platelets aggregate to the site of the injury. They stick together acting as a "plug." Platelets also activate the process which causes a fibrin clot to form, known as secondary hemostasis.
Secondary hemostasis.
3. Platelets alone are not enough to secure the damage in the vessel wall. A clot must form at the site of injury. The formation of a clot depends upon several substances called clotting factors. These factors are designated by roman numerals I through XIII. These factors activate each other in what as known as the clotting cascade. The end result of this cascade is that fibrinogen, a soluble plasma protein, is cleaved into fibrin, a nonsoluble plasma protein. The fibrin proteins stick together forming a clot.
The clotting cascade occurs through two separate pathways that interact, the intrinsic and the extrinsic pathway.

Extrinsic Pathway
The extrinsic pathway is activated by external trauma that causes blood to escape from the vascular system. This pathway is quicker than the intrinsic pathway. It involves factor VII.

Intrinsic Pathway
The intrinsic pathway is activated by trauma inside the vascular system, and is activated by platelets, exposed endothelium, chemicals, or collagen. This pathway is slower than the extrinsic pathway, but more important. It involves factors XII, XI, IX, VIII.

Common Pathway
Both pathways meet and finish the pathway of clot production in what is known as the common pathway. The common pathway involves factors I, II, V, and X.

Instructor's Note: A diagram may be found in your text illustrating the clotting cascade. The student does not need to be concerned about learning the details of these pathways. The student does need to realize that different factors are involved in each pathway. If a patient does not clot normally, it is usually due to a platelet abnormality or deficiency, or by a defect or deficiency in one of the clotting factors. There are diagnostic tests which test for deficiencies in the intrinsic pathway, the extrinsic pathway, and platelet abnormalities. These tests allow the physician to narrow down and eventually discover the defect which is causing a patient to bleed excessively.

The interested student may want to study a more in depth chart and explanation of the coagulation cascade.
See Coagulation Cascade