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Apoptosis: Breaking Up Is Hard To Do

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Apoptosis is the most well-understood mechanism of programmed cell death (PCD). The term apoptosis was coined in 1972 by Kerr et al.4 to describe a form of cell death characterized by nuclear and cytoplasmic condensation followed by the breaking up of the cell into a number of membrane-bound fragments4,6. Apoptosis has traditionally been identified experimentally as a constellation of three features: translocation of phosphatidyl serine to the outer layer of the cell membrane, detected by the acquisition of Annexin V binding, loss of membrane integrity, detected by the inability to exclude vital dyes, and the generation of a characteristic DNA ladder of nucleosome-sized segments6.

Apoptosis is a highly regulated process initiated by specific biochemical signals. There are two main pathways leading to apoptosis: intrinsic and extrinsic2,3,5,7. The intrinsic pathway is triggered by conditions such as DNA damage, ER stress, or hypoxia2,3,7.  It is characterized by mitochondrial outer membrane permeabilization (MOMP), which is regulated by members of the Bcl-2 protein family. BH3 subfamily proteins (BIM, BAD, PUMA, NOXA)7 activate BAX and BAK which cause permeabilization of the mitochondrial outer membrane (MOMP)2,3,7. MOMP results in leakage of cytochrome c, SMAC, and HTRA2 into the cytoplasm. Cytochrome c combines with APAF1 to form a complex called the apoptosome2,3,5. Apoptosome assembly results in the activation of caspase 9 and other initiator caspases, which results in the activation of the executioner caspases, caspases 3 and 7. Progression of apoptosis is negatively regulated by members of the Bcl-2 family including Bcl-2, Bcl-XL, and MCL-13,7, and by the caspase inhibitor XIAP2. When apoptosis is initiated, BH3 proteins block the activity of Bcl-2, and XIAP activity is blocked by SMAC, HTRA2, and ARTS, allowing apoptosis to proceed2.

The extrinsic pathway is triggered by signaling through death receptors such as CD95/FAS and TRAILR2,3,5.  Triggering of these receptors transmits a signal through a receptor-associated protein complex called the death-inducing signaling complex (DISC)5,8. Stimulation of the DISC results in autocatalytic activation of caspases 8 and 10, the initiator caspases for the extrinsic pathway3,5,8. When significant amounts of cFLIP are present in the DISC, activation of caspases 8 and 10 is blocked and apoptosis is inhibited5,8. Activation of Caspases 8 and 10 ultimately leads to activation of caspases 3 and 7, the executioner caspases, where the two pathways merge3,5,8. Activation of caspases 3 and 7 further leads to the final catastrophic events in cell death, including DNA fragmentation, cytoplasmic condensation, and membrane blebbing2,3,5,9.

Recently, regulation of apoptosis has become an exciting target for cancer therapy. Many tumor cells exhibit resistance to apoptosis due to over-expression of Bcl-2-related survival proteins and/or decreased BH3 protein expression1. New drugs known as BH3 mimetics are being developed to inhibit the activity of Bcl-2 survival proteins and enhance BH3-like pro-apoptotic activity in these cells1.




Two main pathways of apoptosis. The intrinsic pathway is initiated by internal stresses such as DNA damage, ER stress, and hypoxia. Major elements of the intrinsic pathway are mitochondrial outer membrane permeability (MOMP), the formation of the apoptosome, and the activation of caspase 9. The external pathway is triggered by engagement of death receptors on the cell surface. Major elements of this pathway are the assembly of the death-inducing signaling complex (DISC) and the activation of caspases 8 and 10. The two pathways converge at the activation of the executioner caspases, 3 and 7, which leads to cell death. Progression of apoptosis via the intrinsic pathway is regulated by the interplay of several Bcl-2 family members, including Bcl-2, the BH3 subfamily, BAX, and BAK, and by the caspase inhibitor XIAP. The primary regulator of the extrinsic pathway is cFLIP, which is part of the DISC.


Below is the current list of Bethyl antibodies involved in cell division:




1. Adams JM, Cory S. 2018. The BCL-2 arbiters of apoptosis and their growing role as cancer targets. Cell Death Differ. Jan;25(1):27-36.

2. Fuchs Y, Steller H. 2015. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat Rev Mol Cell Biol. Jun;16(6):329-344.

3. Ichim G, Tait SW. 2016. A fate worse than death: apoptosis as an oncogenic process. Nat Rev Cancer. Aug;16(8):539-548.

4. Kerr JF, Wyllie AH, Currie AR. 1972. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer Aug;26(4):239-257.

5. Krammer PH, Arnold R, Lavrik IN. 2007. Life and death in peripheral T cells. Nat Rev Immunol. Jul;7(7):532-542.

6. Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G; Nomenclature Committee on Cell Death 2009. 2009. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. Jan;16(1):3-11.

7. Pihán P, Carreras-Sureda A, Hetz C. 2017. BCL-2 family: integrating stress responses at the ER to control cell demise. Cell Death Differ. Sept;24(9):1478-1487.

8. Tsuchiya Y, Nakabayashi O, Nakano H. 2015. FLIP the Switch: Regulation of Apoptosis and Necroptosis by cFLIP. Int J Mol Sci. Dec 18;16(12):30321-30341.

9. Zhang Y, Chen X, Gueydan C, Han J. 2018. Plasma membrane changes during programmed cell deaths. Cell Res. Jan;28(1):9-21.