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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="StatPearls [Internet]" /><meta name="citation_title" content="Apoptosis" /><meta name="citation_publisher" content="StatPearls Publishing" /><meta name="citation_date" content="2024/04/30" /><meta name="citation_author" content="Faisal Akhtar" /><meta name="citation_author" content="Syed Rizwan A. Bokhari" /><meta name="citation_pmid" content="29762996" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK499821/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Apoptosis" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="StatPearls Publishing" /><meta name="DC.Contributor" content="Faisal Akhtar" /><meta name="DC.Contributor" content="Syed Rizwan A. Bokhari" /><meta name="DC.Date" content="2024/04/30" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK499821/" /><meta name="description" content="First identified in the 1970s, apoptosis was considered parallel to mitosis. Many years later, apoptosis is defined as the ATP-dependent, enzyme-mediated, genetically programmed death of cells that are either no longer required or pose a threat to the organism. Apoptosis results when the cytoskeleton (by proteases) and DNA (by endonucleases) break down through several pathways that are homeostatic or pathological. The process maintains homeostasis when cells compromise the organism's survival, but apoptosis does not occur at the appropriate rate or in the correct sequence when the process is no longer regulated. Caspases mediate the process through the downstream effects of the upstream activation by intrinsic and extrinsic pathways, either working separately or simultaneously. " /><meta name="og:title" content="Apoptosis" /><meta name="og:type" content="book" /><meta name="og:description" content="First identified in the 1970s, apoptosis was considered parallel to mitosis. Many years later, apoptosis is defined as the ATP-dependent, enzyme-mediated, genetically programmed death of cells that are either no longer required or pose a threat to the organism. Apoptosis results when the cytoskeleton (by proteases) and DNA (by endonucleases) break down through several pathways that are homeostatic or pathological. The process maintains homeostasis when cells compromise the organism's survival, but apoptosis does not occur at the appropriate rate or in the correct sequence when the process is no longer regulated. Caspases mediate the process through the downstream effects of the upstream activation by intrinsic and extrinsic pathways, either working separately or simultaneously. " /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK499821/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-statpearls-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/statpearls/article-17780/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK499821/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} </style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script>
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. </p></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK499821_"><span class="title" itemprop="name">Apoptosis</span></h1><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Faisal Akhtar</span><sup>1</sup>; <span itemprop="author">Syed Rizwan A. Bokhari</span><sup>2</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup> Ochsner Health Systems</div><div class="affiliation"><sup>2</sup> Tulane Un, Un Med Center New Orleans</div><p class="small">Last Update: <span itemprop="dateModified">April 30, 2024</span>.</p></div><div class="body-content whole_rhythm" itemprop="text"><div id="article-17780.s1"><h2 id="_article-17780_s1_">Introduction</h2><p>First identified in the 1970s, apoptosis was considered parallel to mitosis. Many years later, apoptosis is defined as the ATP-dependent, enzyme-mediated, genetically programmed death of cells that are either no longer required or pose a threat to the organism. Apoptosis results when the cytoskeleton (by proteases) and DNA (by endonucleases) break down through several pathways that are homeostatic or pathological. The process maintains homeostasis when cells compromise the organism's survival, but apoptosis does not occur at the appropriate rate or in the correct sequence when the process is no longer regulated. Caspases mediate the process through the downstream effects of the upstream activation by intrinsic and extrinsic pathways, either working separately or simultaneously. </p><p>This topic highlights the physiological process of apoptosis from the cellular to the systemic level, with clinical correlations to pathological conditions, incorporating current evidence-based literature. The mechanisms of apoptosis are differentiated from necroptosis, pyroptosis, and ferroptosis. In the past few decades, extensive research studies have continued to elucidate the role of apoptosis in regulating cell death and its implications for many recognized medical conditions.</p></div><div id="article-17780.s2"><h2 id="_article-17780_s2_">Causes</h2><p>Current research suggests that apoptosis is one of the predominant cell death mechanisms, summarized below:</p><ul><li class="half_rhythm"><div>Necroptosis: Occurs following activation of tumor necrosis factor-alpha (TNF-α), triggering several cell death receptors.</div></li><li class="half_rhythm"><div>Pyroptosis: Mainly affects cell membrane integrity, engaging inflammasomes to activate caspases.</div></li><li class="half_rhythm"><div>Apoptosis: Differentiated by the release of cytochrome c from<b> </b>the<b> </b>mitochondria, immunologically silent and non-lytic.</div></li><li class="half_rhythm"><div>Ferroptosis: Iron-dependent phospholipid peroxides accumulate in cell membranes, leading to non-apoptotic death.<a class="bk_pop" href="#article-17780.r1">[1]</a><a class="bk_pop" href="#article-17780.r2">[2]</a><a class="bk_pop" href="#article-17780.r3">[3]</a></div></li></ul><p>Given common mid-stream mediators, some researchers do not differentiate necroptosis from apoptosis as a separate mechanism. Instead, the simultaneous process is called PANoptosis, when pyroptosis, apoptosis, and necroptosis occur as programmed cell death. <a class="bk_pop" href="#article-17780.r4">[4]</a> In addition, autophagy refers to the process of digesting organelles or other parts of cells through the machinery of lysosomes, which also leads to cell death.<a class="bk_pop" href="#article-17780.r5">[5]</a> Some parts of apoptosis are considered reversible, referred to as anastasis, particularly in cancer cell lines.<a class="bk_pop" href="#article-17780.r6">[6]</a></p></div><div id="article-17780.s3"><h2 id="_article-17780_s3_">Anatomical Pathology</h2><p>The process of apoptosis is distinct due to the cascade of programmed cell death. Dying cells undergo shrinkage due to disruption of the cell cytoskeleton, mainly caused by caspases. The cells become deeply eosinophilic, shrinking and distancing from their neighbors with the loss of cell-to-cell contact. The nucleus of the dying cell turns deeply basophilic. The hallmark of apoptosis is pyknosis, in which nuclear chromatin condenses to form 1 or more dark-staining masses against the nuclear envelope. Dissolution of the nuclear membrane occurs, and endonuclease slices the DNA into short fragments regularly spaced in size (karyorrhexis).</p><p>Next, this condensed cytoplasm and nucleus break into fragments called apoptotic bodies that bud off from the cell. Macrophages then remove these apoptotic bodies in a process called efferocytosis. The cell membrane remains intact without inflammation, unlike necrosis, pyroptosis, or ferroptosis, where cell swelling and inflammation are common. Macrophages remove apoptotic cells quickly, with little or no inflammation occurring in the surrounding tissues. As such, the mechanism is considered immunologically silent.<a class="bk_pop" href="#article-17780.r7">[7]</a></p></div><div id="article-17780.s4"><h2 id="_article-17780_s4_">Mechanisms</h2><p>Cell proliferation and cell death are balanced in all normal tissues of multicellular organisms. This normal cell death, vital for cell development and health, is called apoptosis and involves the following pathways. All the pathways involve the activation of caspases as the final step.</p><p>
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<b>Intrinsic Pathway</b>
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</p><p>This pathway is activated when the cell undergoes stress from the inside due to various factors such as DNA damage from x-ray or UV light exposure, chemotherapeutic agents, hypoxia, the accumulation of misfolded proteins inside the cell as seen in conditions such as Alzheimer's disease, Parkinson's disease, or Huntington disease, among others. When the cell undergoes stress, cytochrome c leaks from the intermembrane space of mitochondria into the cytosol, which leads to the activation of caspases 9. The regulation of this pathway is governed by the <i>Bcl-2</i> and <i>TP53</i> genes.</p><p>
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<b>Extrinsic Pathway</b>
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</p><p>This pathway is triggered when the cell receives death signals from the other cells. The extrinsic pathway is receptor-linked, and the ligands from the other cells bind to these death receptors on the cell surface, activating apoptosis. This process involves the following cell surface receptors and their corresponding ligands, ultimately activating caspase 8, a key regulator.</p><ul><li class="half_rhythm"><div>TNF-α: TNF-α is a cytokine produced by macrophages and is the major extrinsic mediator of apoptosis. TNF-α binds to the receptor TNFR1, thereby activating caspases.</div></li></ul><ul><li class="half_rhythm"><div>Fas: T cells generate a surface receptor called Fas, which increases production during an infection. After a few days, the activated T lymphocytes release Fas ligands. When Fas binds to these ligands on the same or different cells, apoptosis ensues by activating caspases. Fas receptor, a transmembrane protein of the TNF family, interacts with FasL to activate caspases. Apoptosis aids in the removal of the activated T lymphocytes when the infection has been cleared.</div></li></ul><ul><li class="half_rhythm"><div><i>Bcl-2</i> genes:<b> </b>Located on chromosome 18, anti-apoptotic genes produce protein Bcl-2. Bcl-2 binds to and inhibits APAF-1, preventing the release of cytochrome c from the mitochondria. Cytochrome c is present between inner and outer mitochondrial membranes. Cytochrome c release leads to its binding with APAF-1, activating procaspase 9.</div></li></ul><ul><li class="half_rhythm"><div><i>TP53</i> suppressor gene: This gene encodes a protein that regulates the cell cycle and promotes tumor suppression. If DNA is damaged by ionizing radiation, chemotherapeutic agents, or hypoxia, <i>TP53</i> arrests the cell in the G1 phase of the cell cycle, preventing the proliferation of cells with damaged DNA and facilitating DNA repair. Severe DNA damage prompts apoptosis by activating <i>BAX</i> apoptosis genes. <i>BAX</i> gene products inactivate the <i>Bcl-2</i> anti-apoptosis gene. The balance between pro- and anti-apoptotic genes regulates the process (see <b>Image. </b>DNA Repair and Apoptosis).</div></li></ul><ul><li class="half_rhythm"><div>Cytotoxic CD8+ T-cell pathway:<b> </b>CD8+ T cells secrete perforins, creating holes in the target cells. Subsequently, CD8+ T cells secrete granzymes, which enter the target cells through these holes and activate caspases.</div></li></ul><ul><li class="half_rhythm"><div>Caspases: Caspases are a group of enzymes that are protease in nature. They exist in the cell in an inactive form and require proteolytic cleavage to become active. They are the primary effectors of apoptotic responses, activated by several regulators, as described above.
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<ul><li class="half_rhythm"><div>Initiator caspases include caspases 2, 8, 9, and 10. When activated, the initiator caspases activate the effector caspases.</div></li><li class="half_rhythm"><div>Effector caspases encompass caspases 3, 6, and 7. Active effector caspases cleave several proteins in the cell, leading to cell death and, ultimately, phagocytosis and removal of cellular debris.</div></li><li class="half_rhythm"><div>Of all the caspases, caspase 3 is the most frequently activated one, which catalyzes the cleavage of major cellular proteins and condensation of chromatin. Caspase also activates DNAse enzymes, which causes DNA fragmentation followed by internucleosomal fragmentation.<a class="bk_pop" href="#article-17780.r8">[8]</a><a class="bk_pop" href="#article-17780.r9">[9]</a><a class="bk_pop" href="#article-17780.r10">[10]</a><a class="bk_pop" href="#article-17780.r11">[11]</a></div></li></ul>
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</div></li></ul><p>
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<b>Other Players</b>
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</p><p>Following initial cell death, several danger-associated molecular patterns and pathogen-associated molecular patterns are released from the eliminated cells, signaling additional inflammatory mediators depending on the type of cell death and if other mechanisms are involved. Consequently, whether apoptosis is completely immunologically silent is still debated.<a class="bk_pop" href="#article-17780.r1">[1]</a> Apoptosis proteins are believed to be inhibited in several pathological conditions, particularly cancer, where apoptosis is typically suppressed. These modulators are a family of anti-apoptotic proteins called inhibitors of apoptosis proteins.<a class="bk_pop" href="#article-17780.r12">[12]</a> Cathepsin D is believed to trigger apoptosis, especially during tissue remodeling.<a class="bk_pop" href="#article-17780.r13">[13]</a></p></div><div id="article-17780.s5"><h2 id="_article-17780_s5_">Clinicopathologic Correlations</h2><p>
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<b>Embryogenesis</b>
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</p><p>During embryogenesis in the fetus, the formation of the digits involves the apoptosis of interdigital tissues. Similarly, several body cavities undergo apoptosis in utero.<a class="bk_pop" href="#article-17780.r14">[14]</a> For example, a male fetus loses Mullerian structures due to a Mullerian inhibitory factor synthesized by Sertoli cells.<a class="bk_pop" href="#article-17780.r15">[15]</a> </p><p>
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<b>Menstrual Cycle</b>
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</p><p>The sloughing of the inner lining of the uterus (the endometrium) after the withdrawal of estrogen and progesterone in the menstrual cycle is a physiological process of apoptosis.<a class="bk_pop" href="#article-17780.r16">[16]</a></p><p>
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<b>Immunological Regulation</b>
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</p><ul><li class="half_rhythm"><div>Virus-infected cells: Cytotoxic T cells kill the virus-infected cells by apoptosis.</div></li><li class="half_rhythm"><div>Cells with DNA damage: Cells whose DNA is damaged by radiation exposure or chemotherapeutic agents are arrested in the G1 phase of the cell cycle for repair by <i>p53</i> activation. <i>P53</i> is a tumor suppressor gene. A <i>p53</i> mutation inhibits apoptosis, thus leading to the survival of abnormal cells and the development of carcinomas.</div></li><li class="half_rhythm"><div>Autoreactive T cells:<i> </i>Autoreactive T cells in the thymus are killed by apoptosis.<a class="bk_pop" href="#article-17780.r17">[17]</a></div></li></ul><p>Apoptosis is required for the development and maintenance of a healthy immune system. When B and T lymphocytes are initially produced, they are tested to see if they react against any of the body's self components. Cells that react are killed by apoptosis. If these cells are not removed, self-reactive cells may be released into the body, which can attack tissues and cause autoimmune conditions. Apoptosis is required to turn off the immune system after the offending pathogen is cleared from the body, such as removing acute inflammatory cells, including neutrophils, from healing sites. Furthermore, the destruction of B and T lymphocytes by corticosteroids occurs through apoptosis.</p><p>
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<b>Removal of Misfolded Proteins</b>
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</p><p>The removal of misfolded proteins, such as amyloids and proteins in prion-related diseases, occurs through apoptosis. As a result, several formations that may lead to neurodegenerative diseases are eliminated.</p></div><div id="article-17780.s6"><h2 id="_article-17780_s6_">Clinical Significance</h2><p>
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<b>Tumorigenesis</b>
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</p><p>A decrease in apoptosis results in higher cell survival rates, leading to the development of cancers. In follicular lymphoma, a translocation event relocates the <i>Bcl-2</i> gene from chromosome 18 to chromosome 14, leading to excessive transcription and increased levels of <i>Bcl-2. </i>This excess <i>Bcl-2</i> gene inhibits APAF-1, consequently inactivating caspases and intrinsic apoptosis, leading to follicular lymphoma. Mutation or deletion of <i>p53</i> genes increases the chances of developing a tumor, as the cells with damaged DNA divide uncontrolled.</p><p>Factors such as exposure to chemicals, radiation, and viruses can damage the <i>p53 </i>gene. Individuals with Li-Fraumeni syndrome have only 1 functional copy of <i>p53;</i> therefore, they are more likely to develop a tumor in early adulthood. When DNA repair mechanisms fail to remove the damaged, translocated, or deleted DNA, cells begin to evade cell cycle checkpoints that lead to apoptosis (see <b>Image. </b>The<b> </b>Mechanism of Apoptosis).<a class="bk_pop" href="#article-17780.r15">[15]</a><a class="bk_pop" href="#article-17780.r18">[18]</a><a class="bk_pop" href="#article-17780.r19">[19]</a></p><p>
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<b>Autoimmune Diseases</b>
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</p><p>A decrease in the apoptosis of self-reactive immune cells can lead to the development of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and autoimmune lymphoproliferative syndrome.<a class="bk_pop" href="#article-17780.r20">[20]</a> Recently, the role of mitochondria in regulating cell death has been linked to the development of diabetes due to the destruction of β-cells.<a class="bk_pop" href="#article-17780.r21">[21]</a></p><p>
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<b>Neurodegenerative Diseases</b>
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</p><p>Cell death has also been implicated in many neurodegenerative disorders. Necrosis and apoptosis occur in neurologic diseases such as acute ischemic syndrome. In chronic neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, and Huntington's disease, neuronal cell death predominantly occurs through apoptosis and has been implicated.</p><p>
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<b>Cardiovascular Diseases</b>
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</p><p>Necrosis was long considered the sole cause of myocardial infarction. However, recent studies have shown that apoptosis also occurs mainly during the reperfusion phase after the acute infarction, leading to further myocardial damage. Staging atherosclerotic plaques and rupture is correlated to apoptosis, specifically the death of macrophages.<a class="bk_pop" href="#article-17780.r5">[5]</a><a class="bk_pop" href="#article-17780.r22">[22]</a></p><p>
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<b>Therapeutic Implications</b>
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</p><p>Given the correlation of physiological and pathological processes, the identified players in intrinsic and extrinsic apoptosis are targets for immunotherapy.<a class="bk_pop" href="#article-17780.r9">[9]</a> Several cancer therapies inhibit <i>Bcl-2</i>, which is the most notorious example.<a class="bk_pop" href="#article-17780.r23">[23]</a> Given the multilevel effects of apoptotic pathways, no one specific therapeutic innovation has set the standard. Recently, a TUNEL assay was used to measure apoptotic cell death, which is pertinent when staging pathological tissue samples.<a class="bk_pop" href="#article-17780.r6">[6]</a> Similarly, the applicability of antibody-specific inhibitors to malignant tumor antigens is perhaps the next level of treatment specificity.<a class="bk_pop" href="#article-17780.r4">[4]</a></p></div><div id="article-17780.s7"><h2 id="_article-17780_s7_">Review Questions</h2><ul><li class="half_rhythm"><div>
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<a href="https://www.statpearls.com/articlelibrary/commentarticle/17780/?utm_source=pubmed&utm_campaign=comments&utm_content=17780" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Comment on this article.</a>
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</div></li></ul></div><div class="floats-group" id="article-17780.s8"></div><div class="floats-group" id="article-17780.s9"></div><div id="article-17780.s10"><h2 id="_article-17780_s10_">References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="article-17780.r1">Bertheloot D, Latz E, Franklin BS. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. <span><span class="ref-journal">Cell Mol Immunol. </span>2021 May;<span class="ref-vol">18</span>(5):1106-1121.</span> [<a href="/pmc/articles/PMC8008022/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8008022</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33785842" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33785842</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="article-17780.r2">Ketelut-Carneiro N, Fitzgerald KA. Apoptosis, Pyroptosis, and Necroptosis-Oh My! The Many Ways a Cell Can Die. <span><span class="ref-journal">J Mol Biol. </span>2022 Feb 28;<span class="ref-vol">434</span>(4):167378.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/34838807" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 34838807</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="article-17780.r3">Samir P, Malireddi RKS, Kanneganti TD. The PANoptosome: A Deadly Protein Complex Driving Pyroptosis, Apoptosis, and Necroptosis (PANoptosis). <span><span class="ref-journal">Front Cell Infect Microbiol. </span>2020;<span class="ref-vol">10</span>:238.</span> [<a href="/pmc/articles/PMC7283380/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7283380</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32582562" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32582562</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="article-17780.r4">Newton K, Strasser A, Kayagaki N, Dixit VM. Cell death. <span><span class="ref-journal">Cell. </span>2024 Jan 18;<span class="ref-vol">187</span>(2):235-256.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/38242081" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 38242081</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="article-17780.r5">Li M, Wang ZW, Fang LJ, Cheng SQ, Wang X, Liu NF. Programmed cell death in atherosclerosis and vascular calcification. <span><span class="ref-journal">Cell Death Dis. </span>2022 May 18;<span class="ref-vol">13</span>(5):467.</span> [<a href="/pmc/articles/PMC9117271/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9117271</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35585052" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35585052</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="article-17780.r6">Mirzayans R, Murray D. Do TUNEL and Other Apoptosis Assays Detect Cell Death in Preclinical Studies? <span><span class="ref-journal">Int J Mol Sci. </span>2020 Nov 29;<span class="ref-vol">21</span>(23)</span> [<a href="/pmc/articles/PMC7730366/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7730366</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33260475" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33260475</span></a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="article-17780.r7">Sorice M. Crosstalk of Autophagy and Apoptosis. <span><span class="ref-journal">Cells. </span>2022 Apr 28;<span class="ref-vol">11</span>(9)</span> [<a href="/pmc/articles/PMC9102887/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9102887</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35563785" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35563785</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="article-17780.r8">Hu SJ, Jiang SS, Zhang J, Luo D, Yu B, Yang LY, Zhong HH, Yang MW, Liu LY, Hong FF, Yang SL. Effects of apoptosis on liver aging. <span><span class="ref-journal">World J Clin Cases. </span>2019 Mar 26;<span class="ref-vol">7</span>(6):691-704.</span> [<a href="/pmc/articles/PMC6448073/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6448073</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30968034" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30968034</span></a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="article-17780.r9">Nguyen TT, Wei S, Nguyen TH, Jo Y, Zhang Y, Park W, Gariani K, Oh CM, Kim HH, Ha KT, Park KS, Park R, Lee IK, Shong M, Houtkooper RH, Ryu D. Mitochondria-associated programmed cell death as a therapeutic target for age-related disease. <span><span class="ref-journal">Exp Mol Med. </span>2023 Aug;<span class="ref-vol">55</span>(8):1595-1619.</span> [<a href="/pmc/articles/PMC10474116/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10474116</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/37612409" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 37612409</span></a>]</div></dd><dt>10.</dt><dd><div class="bk_ref" id="article-17780.r10">Lee SB, Lee S, Park JY, Lee SY, Kim HS. Induction of p53-Dependent Apoptosis by Prostaglandin A<sub>2</sub>. <span><span class="ref-journal">Biomolecules. </span>2020 Mar 24;<span class="ref-vol">10</span>(3)</span> [<a href="/pmc/articles/PMC7175137/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7175137</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32213959" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32213959</span></a>]</div></dd><dt>11.</dt><dd><div class="bk_ref" id="article-17780.r11">Baena-Lopez LA, Wang L, Wendler F. Cellular stress management by caspases. <span><span class="ref-journal">Curr Opin Cell Biol. </span>2024 Feb;<span class="ref-vol">86</span>:102314.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/38215516" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 38215516</span></a>]</div></dd><dt>12.</dt><dd><div class="bk_ref" id="article-17780.r12">Michie J, Kearney CJ, Hawkins ED, Silke J, Oliaro J. The Immuno-Modulatory Effects of Inhibitor of Apoptosis Protein Antagonists in Cancer Immunotherapy. <span><span class="ref-journal">Cells. </span>2020 Jan 14;<span class="ref-vol">9</span>(1)</span> [<a href="/pmc/articles/PMC7017284/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7017284</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31947615" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31947615</span></a>]</div></dd><dt>13.</dt><dd><div class="bk_ref" id="article-17780.r13">Duarte-Olivenza C, Moran G, Hurle JM, Lorda-Diez CI, Montero JA. Lysosomes, caspase-mediated apoptosis, and cytoplasmic activation of P21, but not cell senescence, participate in a redundant fashion in embryonic morphogenetic cell death. <span><span class="ref-journal">Cell Death Dis. </span>2023 Dec 09;<span class="ref-vol">14</span>(12):813.</span> [<a href="/pmc/articles/PMC10710412/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10710412</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/38071330" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 38071330</span></a>]</div></dd><dt>14.</dt><dd><div class="bk_ref" id="article-17780.r14">Nössing C, Ryan KM. 50 years on and still very much alive: 'Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics'. <span><span class="ref-journal">Br J Cancer. </span>2023 Feb;<span class="ref-vol">128</span>(3):426-431.</span> [<a href="/pmc/articles/PMC9938139/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9938139</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/36369364" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36369364</span></a>]</div></dd><dt>15.</dt><dd><div class="bk_ref" id="article-17780.r15">Yin S, Ji C, Wu P, Jin C, Qian H. Human umbilical cord mesenchymal stem cells and exosomes: bioactive ways of tissue injury repair. <span><span class="ref-journal">Am J Transl Res. </span>2019;<span class="ref-vol">11</span>(3):1230-1240.</span> [<a href="/pmc/articles/PMC6456565/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6456565</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30972158" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30972158</span></a>]</div></dd><dt>16.</dt><dd><div class="bk_ref" id="article-17780.r16">Verma R, Verma P, Budhwar S, Singh K. S100 proteins: An emerging cynosure in pregnancy & adverse reproductive outcome. <span><span class="ref-journal">Indian J Med Res. </span>2018 Dec;<span class="ref-vol">148</span>(Suppl):S100-S106.</span> [<a href="/pmc/articles/PMC6469379/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6469379</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30964086" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30964086</span></a>]</div></dd><dt>17.</dt><dd><div class="bk_ref" id="article-17780.r17">Mehrbod P, Ande SR, Alizadeh J, Rahimizadeh S, Shariati A, Malek H, Hashemi M, Glover KKM, Sher AA, Coombs KM, Ghavami S. The roles of apoptosis, autophagy and unfolded protein response in arbovirus, influenza virus, and HIV infections. <span><span class="ref-journal">Virulence. </span>2019 Dec;<span class="ref-vol">10</span>(1):376-413.</span> [<a href="/pmc/articles/PMC6527025/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6527025</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30966844" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30966844</span></a>]</div></dd><dt>18.</dt><dd><div class="bk_ref" id="article-17780.r18">McBride A, Houtmann S, Wilde L, Vigil C, Eischen CM, Kasner M, Palmisiano N. The Role of Inhibition of Apoptosis in Acute Leukemias and Myelodysplastic Syndrome. <span><span class="ref-journal">Front Oncol. </span>2019;<span class="ref-vol">9</span>:192.</span> [<a href="/pmc/articles/PMC6445951/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6445951</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30972300" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30972300</span></a>]</div></dd><dt>19.</dt><dd><div class="bk_ref" id="article-17780.r19">Çıkla-Süzgün P, Küçükgüzel ŞG. Recent Advances in Apoptosis: THE Role of Hydrazones. <span><span class="ref-journal">Mini Rev Med Chem. </span>2019;<span class="ref-vol">19</span>(17):1427-1442.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30968776" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30968776</span></a>]</div></dd><dt>20.</dt><dd><div class="bk_ref" id="article-17780.r20">Angelousi A, Kassi E, Ansari-Nasiri N, Randeva H, Kaltsas G, Chrousos G. Clock genes and cancer development in particular in endocrine tissues. <span><span class="ref-journal">Endocr Relat Cancer. </span>2019 Jun;<span class="ref-vol">26</span>(6):R305-R317.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30959483" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30959483</span></a>]</div></dd><dt>21.</dt><dd><div class="bk_ref" id="article-17780.r21">Kabra UD, Jastroch M. Mitochondrial Dynamics and Insulin Secretion. <span><span class="ref-journal">Int J Mol Sci. </span>2023 Sep 07;<span class="ref-vol">24</span>(18)</span> [<a href="/pmc/articles/PMC10530730/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10530730</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/37762083" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 37762083</span></a>]</div></dd><dt>22.</dt><dd><div class="bk_ref" id="article-17780.r22">Ge ZD, Lian Q, Mao X, Xia Z. Current Status and Challenges of NRF2 as a Potential Therapeutic Target for Diabetic Cardiomyopathy. <span><span class="ref-journal">Int Heart J. </span>2019 May 30;<span class="ref-vol">60</span>(3):512-520.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30971629" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30971629</span></a>]</div></dd><dt>23.</dt><dd><div class="bk_ref" id="article-17780.r23">D'Addio F, Montefusco L, Lunati ME, Pastore I, Assi E, Petrazzuolo A, Marin V, Bruckmann C, Fiorina P. Targeting a novel apoptotic pathway in human disease. <span><span class="ref-journal">Bioessays. </span>2023 Jun;<span class="ref-vol">45</span>(6):e2200231.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/36998110" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36998110</span></a>]</div></dd></dl></div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_top_margin">
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<b>Disclosure: </b>Faisal Akhtar declares no relevant financial relationships with ineligible companies.</p></div></dd><dt></dt><dd><div><p class="no_top_margin">
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<b>Disclosure: </b>Syed Rizwan Bokhari declares no relevant financial relationships with ineligible companies.</p></div></dd></dl></div><div class="bk_prnt_sctn"><h2>Figures</h2><div class="whole_rhythm bk_prnt_obj bk_first_prnt_obj"><div id="article-17780.image.f1" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=DNA%20Repair%20and%20Apoptosis&p=BOOKS&id=499821_Antiapoptotic.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK499821/bin/Antiapoptotic.jpg" alt="DNA Repair and Apoptosis" class="tileshop" title="Click on image to zoom" /></a></div><div class="caption"><p>DNA Repair and Apoptosis. DNA repair reinstates a cell to its normal state, whereas apoptosis eliminates a cell without inflammation. Defective DNA repair and apoptosis allow the cell to initiate uncontrolled proliferation through promotion and subsequent progression, resulting in distant tissue invasion. Contributed by S Abd El Fattah, MD</p></div></div></div><div class="whole_rhythm bk_prnt_obj"><div id="article-17780.image.f2" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Mechanism%20of%20Apoptosis&p=BOOKS&id=499821_Image__2.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK499821/bin/Image__2.jpg" alt="Mechanism of Apoptosis" class="tileshop" title="Click on image to zoom" /></a></div><div class="caption"><p>Mechanism of Apoptosis. When DNA repair fails, apoptosis ensues to eliminate the corrupt cell without inflammation. An initiated cell evades tumor suppressor genes and activates constitutional proliferation (auto-proliferation). Subsequently, the initiated cell is promoted through the acquisition of additional mutations. This mutation immortalizes the cell by skipping immune checkpoints. Additional mutations are acquired, facilitating distant tissue invasion. SA Ibrahim, MBBCh, MSc, PhD</p></div></div></div></div></div></div>
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