The falling of leaves, the disappearance of tadpoles' tails during their transformation into frogs – these seemingly ordinary natural phenomena are all intimately tied to a cellular phenomenon known as "cell apoptosis." What exactly is "cell apoptosis," and how does it occur?
This article aims to concisely summarize the key points surrounding cell apoptosis.
▇ Definition and Significance of Cell Apoptosis
Apoptosis refers to a biochemical process characterized by the programmed transmission of death-inducing signals through the interaction of specific proteins, leading to cellular breakdown. It is widely present in multicellular organisms and is an essential physiological process for embryonic development, tissue homeostasis, and organism stability. The morphological features of apoptosis include chromatin condensation and nuclear DNA fragmentation, ultimately resulting in clearance by macrophages.
Apoptosis is a form of programmed cell death that does not induce an inflammatory response. It is a self-regulated mechanism that removes unwanted cells (such as those undergoing tumor necrosis or autoreactive lymphocytes) to maintain balance within the body.
Studying apoptosis helps elucidate the mechanisms behind various diseases, including autoimmune disorders, neurodegenerative diseases, bacterial and viral infections, heart disease, and cancer. Therefore, clinical research on apoptosis is closely linked to tackling multiple diseases.
▇ The Process of Cell Apoptosis
Cell apoptosis generally includes 3 stages:
1. Initiation Stage: The target cell receives a death signal and begins programmed cell death.
2. Execution Stage: A series of morphological and biochemical changes occur within the cell, such as nuclear condensation, cell shrinkage, membrane blebbing, loss of microvilli, degradation of chromosomal DNA, and the formation of DNA fragments organized into nucleosomal units.
3. Phagocytic Stage: Apoptotic bodies are engulfed and digested by surrounding phagocytic cells, completing the process of apoptosis.
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▇ Key Factors Related to Apoptosis
Several genes and proteins play crucial roles in the process of apoptosis. In experiments such as Western Blot (WB), Immunohistochemistry (IHC), and Immunofluorescence (IF), corresponding antibodies are used to establish a connection with the proteins being studied, thereby providing information on protein expression localization and relative expression levels.
1. Bcl-2 Family
Since the discovery of the B-cell lymphoma-2 (Bcl-2) gene in 1985, several other highly homologous molecules have been identified, all classified as Bcl-2 family proteins. Bcl-2 has been approved by the U.S. Food and Drug Administration as a target for anticancer drugs, highlighting the significant potential of Bcl-2 family proteins in apoptosis research.
The Bcl-2 family is an important group of proteins that regulate apoptosis, comprising both pro-apoptotic proteins (such as BH3-only, Bax, Bak, and Bok) and anti-apoptotic proteins (like Bcl-2 and Bcl-w). These two classes of proteins coordinate with each other during apoptosis, jointly determining whether a cell will enter the apoptotic program by mediating signals through the mitochondrial pathway.
2. Caspase Family
The caspase family consists of genes that encode the main enzymes promoting apoptosis. Apoptotic caspases can be classified into two categories: initiator caspases (Caspase 8, 9, and 10) and executioner caspases (Caspase 3, 6, and 7). Among these, Caspase 8 and Caspase 10 are initiators of extrinsic apoptosis, while Caspase 9 initiates intrinsic apoptosis.
Function Classification and Domain Structure of Caspases in Mice and Humans
(Image from reference 2)
3. Cytochrome C
Cytochrome C is a protein that belongs to Class 1 of the C-type cytochrome family. It plays a crucial role in apoptosis. Once released into the cytosol, Cytochrome C binds to Apaf-1, activating pro-Caspase 9 and triggering a cascade of apoptosis-related enzymes.
4. Apaf-1
Apoptotic protease-activating factor 1 (Apaf-1) typically exists in an inactive monomeric form. Apaf-1 is a downstream component of p53 in tumor cell apoptosis and is involved in the mitochondrial-mediated apoptosis pathway. Following the initiation of apoptotic signals, Apaf-1 is activated and assembles with other proteins to form the apoptosome. The apoptosome activates Caspase-9, which in turn activates other caspases, ultimately leading to cell apoptosis.
5. AIF
Apoptosis-inducing factor (AIF) is a protein that typically resides between the inner and outer membranes of mitochondria, with its N-terminus anchored to the inner membrane and its C-terminus free in the intermembrane space. AIF plays a role in maintaining mitochondrial structure and stabilizing the respiratory chain. Upon apoptotic stimulation, the N-terminus of AIF is cleaved, allowing AIF to be released from the mitochondria into the cytosol, and subsequently entering the nucleus. In the nucleus, AIF recruits proteases and nucleases, leading to the degradation of chromatin and DNA, ultimately resulting in cell apoptosis.
6. XIAP and Smac/DIABLO
X-linked inhibitor of apoptosis (XIAP) is a member of the apoptosis inhibitor protein family, capable of blocking caspase-induced apoptosis.
The second mitochondria-derived activator of caspase (Smac), also known as DIABLO (direct IAP binding protein with low isoelectric point), is an endogenous mitochondrial pro-apoptotic protein. Smac/DIABLO inhibits the release of inhibitor of apoptosis proteins (IAPs). With reduced IAP release, this promotes the activation of apoptotic proteins Caspase-3, -6, and -7, leading to apoptosis.
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▇ References
1. Xuebo Xu, Yueyang Lai, Zi-Chun Hua. Apoptosis and apoptotic body: disease message and therapeutic target potentials.Biosci Rep.2019 Jan 18;39(1):BSR20180992.doi: 10.1042/BSR20180992. Print 2019 Jan 31.
2. Nina Van Opdenbosch, Mohamed Lamkanfi.Caspases in Cell Death, Inflammation, and Disease.Immunity. 2019 Jun 18;50(6):1352-1364. doi: 10.1016/j.immuni.2019.05.020.
3. Roberto Santucci,Federica Sinibaldi,Paola Cozza , Fabio Polticelli , Laura Fiorucci.Cytochrome c: An extreme multifunctional protein with a key role in cell fate.Int J Biol Macromol. 2019 Sep 1;136:1237-1246. doi: 10.1016/j.ijbiomac.2019.06.180. Epub 2019 Jun 25.
4. Swaroop Kumar Pandey , Avijit Paul ,Et al.SMAC/Diablo controls proliferation of cancer cells by regulating phosphatidylethanolamine synthesis.Mol Oncol. 2021 Nov;15(11):3037-3061.doi: 10.1002/1878-0261.12959. Epub 2021 May 4.
5. Sang-Hyun Park , Sanggil Kim , Hyun Soo Lee , Injae Shin. Real-Time Spatial and Temporal Analysis of the Translocation of the Apoptosis-Inducing Factor in Cells. ACS Chem Biol.2021 Nov 19;16(11):2462-2471. doi: 10.1021/acschembio.1c00565. Epub 2021 Oct 25.
6. Hu, S.M., Wang, Y.N., Xu, Z.M., Zhou, J.L. Research progress on the role of Bcl-2 family molecules in apoptosis. Advances in Animal Medicine. 2021; 42(10).
7. Li, M., Lin, J. Apoptotic pathways and their mechanisms. International Journal of Obstetrics and Gynecology. 2014; 41(02).
8. Cai, Z.Y., Pan, Y.W., Shang, Y.W., Wang, S.B., Zhang, W.J. Research progress on XIAP and Smac. Chinese Journal of Surgical Oncology. 2014; 6(01).
