Information

In what ways can mechanisms of apoptosis be damaged?

In what ways can mechanisms of apoptosis be damaged?



We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

How many ways can an Apoptosis mechanism be made disfunctional or irreparably damaged? If a cell has damaged Apoptosis mechanisms and it divides will its daughter cells have such damage?


Most of us have had the apoptotic process in our B-lymphocytes disrupted when we had infectious mononucleosis, caused by the EBV virus. The EBV virus (pardon the virus-virus) encodes proteins, including one that mimics a host cell protein, Bcl-2, which plays an important role in apoptosis. The set of virus 'decoy' proteins forces the infected cell to survive and be a host to produce new virus, whereas the cell's normal response would be to apoptose. Wart viruses such as HPV may have similar mechanisms.

So in summary, excessive growth or transformation to an immortal cell typically requires activation of mechanisms that promote cell growth and the inibition of mechanisms that promote cell death. "Transforming viruses' often have mechanisms to affect both cell growth and cell death.

This answer isn't to the question 'how many ways can [the] apoptosis mechanism [… ] be damaged ', but answers 'what's a common way that apoptosis pathways can be disrupted'… large DNA transforming viruses.


Lot's of ways. Apoptosis is complex, but falls under two pathways ending up at caspase 3. Anywhere in the pathway may there be a problem but also in things that trigger the pathway. For example in cancer there is loss of tumour suppressors which ensure a damaged cell undergoes apoptosis or prevents replication and oncogenes which allow controlled replication. Damage to these genes allows a cell to divide in the absence of signals to divide and also forget to check that it's DNA isn't damaged before replicating. This is then passed on to the daughter cancer cells. As each check is removed the cell permits more and more mutations meaning more and more likelihood for the next mutation to occur. Cancer is caused literally by one cell having defects and every daughter cell also possess the defects. Those that have defects which accidentally kill the cell are selected out.


Apoptosis plays a fundamental role in many physiological processes such as tissue development, and the immune response. Thus, regulation of apoptosis is important for tissue homeostasis and its deregulation can lead to a variety of pathological conditions including carcinogenesis and chemo-resistance.

Apoptosis is mediated primarily through promoting or inhibiting the activation of caspases. Caspases are effectors of cell suicide and cleave multiple substrates, leading to biochemical and morphological changes including mitochondrial outer membrane permeabilization, cell membrane remodeling and blebbing, cell shrinkage, nuclear condensation, and DNA fragmentation.

In mammalian systems, the extrinsic death receptor pathway, the intrinsic mitochondrial pathway and endoplasmic reticulum pathway are the major signaling systems that result in the activation of the executioner/effector caspases and the consequent demise of the cell.

All pathways eventually lead to a common pathway or the execution phase of apoptosis. Understanding the apoptosis mechanisms is important and helpful to us in the understanding of the pathogenesis of conditions as a result of disordered apoptosis. Meanwhile, it may help in the development of drugs that target certain apoptotic genes or pathways.


References

Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 201335:495–516.

Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 197226:239–57.

Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis. 200021:485–95.

Horvitz HR. Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cancer Res. 199959:1701–6.

Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 199510:1456–62.

Krauss G. Biochemistry of signal transduction and regulation. Ed:VCH Wiley, 3 rd Edition. 2003511–531.

Power C, Fanning N, Redmond HP. Cellular apoptosis and organ injury in sepsis: a review. Shoch. 200218:197–211.

Savill J, Fadok V. Corpse clearance defines the meaning of cell death. Nature. 2000407:784–8.

Rosenblatt J, Raff MC, Cramer LP. An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin- and myosin-dependent mechanism. Curr Biol. 201111:1847–57.

Ferri KF, Kroemer G. Organelle-specific initiation of cell death pathways. Nat Cell Biol. 20013:255–63.

Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol. 1995146:3–15.

Liu X, Li P, Widlak P, et al. The 40-kDa subunit of DNA fragmentation factor induces DNA fragmentation and chromatin condensation during apoptosis. Proc Natl Acad Sci U S A. 199895:8461–6.

Grimsley C, Ravichandran KS. Cues for apoptotic cell engulfment: eat-me, don’t-eat-me and come-get-me signals. Trends Cell Biol. 200313:648–56.

Mashima T, Naito M, Noguchi K, Miller DK, Nicholson DW, Tsuruo T. Actin cleavage by CPP-32/apopain during the development of apoptosis. Oncogene. 199714:1007–12.

Ziegler U, Groscurth P. Morphological features of cell death. Physiology. 200410:124–8.

Wang X. The expanding role of mitochondria in apoptosis. Genes Dev. 200115:2922–33.

Thornberry NA, Lazebnik Y. Caspases: enemies within. Science. 1998281:1312–6.

Hengartnere MO. The biochemistry of apoptosis. Nature. 2000407:770–6.

Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin. 200555:178–94.

Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P. Toxic proteins released from mitochondria in cell death. Oncogene. 200423:2861–74.

Du C, Fang M, Li Y, Li L, Wang X. SMAC, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000102:33–42.

Chinnaiyan AM. The apoptosome: heart and soul of the cell death machine. Neoplasia. 19991:5–15.

Hill MM, Adrain C, Duriez PJ, Creagh EM, Martin SJ. Analysis of the composition, assembly kinetics and activity of native Apaf-1 apoptosomes. Embo J. 200423:2134–45.

Susin SA, Daugas E, Ravagnan L, et al. Two distinct pathways leading to nuclear apoptosis. J Exp Med. 2000192:571–80.

Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 20022:647–56.

Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001104:487–501.

Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 199581:495–50.

Wajant H. The Fas signaling pathway: more than a paradigm. Science. 2002296:1635–6.

Sax JK, Fei P, Murphy ME, Bernhard E, Korsmeyer SJ, El-Deiry WS. BID regulation by p53 contributes to chemosensitivity. Nat Cell Biol. 20024:842–9.

Hitoshi Y, Lorens J, Kitada SI, et al. Toso, a cell surface, specific regulator of Fas-induced apoptosis in T cells. Immunity. 19988:461–71.

Scaffidi C, Schmitz I, Krammer PH, Peter ME. The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem. 1999274:1541–8.

Kuranaga E. Beyond apoptosis: caspase regulatory mechanisms and functions in vivo. Genes Cells. 201217:83–97.

Yuan J, Shaham S, Ledoux S, Ellis HM, The HHR. The C. elegans cell death gene Ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell. 199375:641–52.

Ellis HM, Horvitz HR. Genetic control of programmed cell death in the nematode C. elegans. Cell. 198644:817–29.

Shi Y. Mechanisms of caspase inhibition and activation during apoptosis. Mol Cell. 20029:459–70.

Chowdhury I, Tharakan B, Bhat GK. Caspases—an update. Comp Biochem Physiol. 2008151:10–27.

Yan N, Shi Y. Mechanisms of apoptosis through structural biology. Annu Rev Cell Dev Biol. 200521:35–56.

Los M, Stroh C, Janicke RU, Schulze-Osthoff K. Caspases: more than just killers? Trends Immunol. 200122:31–4.

Martinon F, Tschopp J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell. 2004117:561–74.

Los M, van de Craen M, Penning CL, et al. Requirement of an ICE/CED-3 protease for Fas/APO-1-1 mediated apoptosis. Nature. 199537:81–3.

Fantuzzi G, Puren AJ, Harding MW, Livingston DJ, Dinarello CA. Interleukin-18 regulation of interferon gamma production and cell proliferation as shown in interleukin-1beta-converting enzyme (caspase-1)-deficient mice. Blood. 199891:2118–25.

Vakifahmetoglu-Norberg H, Zhivotovsky B. The unpredictable caspase-2: what can it do? Trends Cell Biol. 201020:150–9.

Paroni G, Henderson C, Schneider C, Brancolini C. Caspase-2-induced apoptosis is dependent on caspase-9, but its processing during UV- or tumor necrosis factor-dependent cell death requires caspase-3. J Biol Chem. 2001276:21907–15.

Van de Craen M, Declercq W. Van den brande I, Fiers W, Vandenabeele P. The proteolytic procaspase activation network: an in vitro analysis. Cell Death Differ. 19996:1117–24.

Tinel A, Tschopp J. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science. 2004304:843–6.

Degterev A, Boyce M, Yuan J. A decade of caspases. Oncogene. 200322:8543–67.

Porter AG, Janicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 19996:99–104.

Slee EA, Adrain C, Martin SJ. Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem. 2001276:7320–6.

Lakhani SA, Masud A, Kuida K, et al. Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science. 2006311:847–51.

Lamkanfi M, Kanneganti TD. Caspase-7: a protease involved in apoptosis and inflammation. Int J Biochem Cell Biol. 201042:21–4.

Ghavami S, Eshraghi M, Kadkhoda K, et al. Role of BNIP3 in TNF-induced cell death—TNF upregulates BNIP3 expression. Biochim Biophys Acta. 17932009:546–60.

Carrington PE, Sandu C, Wei Y, et al. The structure of FADD and its mode of interaction with procaspase-8. Mol Cell. 200622:599–610.

Ghavami S, Hashemi M, Ande SR, et al. Apoptosis and cancer: mutations within caspase genes. J Med Genet. 200946:497–510.

Micheau O, Thome M, Schneider P, et al. Gr ̈utter MG. The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex. J Biol Chem. 2002277:45162–71.

Irmler M, Thome M, Hahne M, et al. Inhibition of death receptors signals by cellular FLIP. Nature. 1997388:190–5.

Boatright KM, Deis C, Denault JB, Sutherlin DP, Salvesen GC. Activation of caspases-8 and -10 by FLIP (L). Biochem J. 2004382:651–7.

Pop C, Oberst A, Drag M, et al. FLIP (L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity. Biochem J. 2011433:447–57.

Chang DW, Xing Z, Pan Y, et al. c-FLIP8(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. EMBO J. 200221:3704–14.

Rodriguez J, Lazebnik Y. Caspase-9 and APAF-1 form an active holoenzyme. Genes Dev. 199913:3179–84.

Qin H, Srinivasula SM, Wu G, Fernandes-Alnemri T, Alnemri ES, Shi Y. Structural basis of procaspase-9 recruitment by the apoptotic protease-activating factor 1. Nature. 1999399:549–57.

Crook NE, Clem RJ, Miller LK. An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J Virol. 199367:2168–74.

Kaiser WJ, Vucic D, Miller LK. The Drosophila inhibitor of apoptosis D-IAP1 suppresses cell death induced by the caspase drICE. FEBS Lett. 1998440:243–8.

Eckelman BP, Salvesen GS. The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases. J Biol Chem. 2006281:3254–60.

Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 19973:917–22.

Banks DP, Plescia J, Altieri DC, et al. Survivin does not inhibit caspase-3 activity. Blood. 200096:4002–3.

Saleem M, Qadir MI, Perveen N, et al. Inhibitors of apoptotic proteins: new targets for anticancer therapy. Chem Biol Drug Des. 201382:243–51.

Sun C, Cai M, Gunasekera AH, et al. NMR structure and mutagenesis of the inhibitor-of-apoptosis protein XIAP. Nature. 1999401:818–21.

Sun CH, Cai ML, Meadows RP, et al. NMR structure and mutagenesis of the third Bir domain of the inhibitor of apoptosis protein XIAP. J Biol Chem. 2000275:33777–81.

Vaux DL, Silke J. IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol. 20056:287–97.

Salvesen GS, Duckett CS. IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol. 20003:401–10.

Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y. Structural and biochemical basis of apoptotic activation by SMAC/DIABLO. Nature. 2000406:855–62.

Srinivasula SM, Hegde R, Saleh A, et al. A conserved XIAP- interaction motif in caspase-9 and SMAC/DIABLO regulates caspase activity and apoptosis. Nature. 2001410:112–6.

Yoo NJ, Kim HS, Kim SY, et al. Immunohistochemical analysis of SMAC/DIABLO expression in human carcinomas and sarcomas. APMIS. 2003111:382–8.

Yang QH, Church-Hajduk R, Ren J, Newton ML, Du C. Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis [IAP] irreversibly inactivates IAPs and facilitates caspase activity in apoptosis. Genes Dev. 200317:1487–96.

Liston P, Fong WG, Kelly NL, et al. Identification of XAF1 as an antagonist of XIAP anti-caspase activity. Nat Cell Biol. 20013:28–133.

Ma TL, Ni PH, Zhong J, Tan JH, Qiao MM, Jiang SH. Low expression of XIAP- associated factor 1 in human colorectal cancers. Chin J Dig Dis. 20056:10–4.

Gross A, Mcdonnell JM, Korsmeyer SJ. Bcl-2 family members and the mitochondria in apoptosis. Genes Dev. 199913:1899–911.

Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the Bcl-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 20145:49–63.

Pepper C, Bently P. The role of the Bcl-2 family in the modulation of apoptosis. Symp Soc Exp Biol. 200052:43–53.

Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science. 2004305:626–9.

Frenzel A, Grespi F, Chmelewskij W, Villunger A. Bcl2 family proteins in carcinogenesis and the treatment of cancer. Apoptosis. 200914:584–96.

Camisasca DR, Honorato J, Bernardo V, et al. Expression of Bcl-2 family proteins and associated clinicopathologic factors predict survival outcome in patients with oral squamous cell carcinoma. Oral Oncol. 200945:225–33.

Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 200915:126–1132.

Lessene G, Czabotar PE, Colman PM. Bcl-2 family antagonists for cancer therapy. Nat Rev Drug Discov. 20087:989–1000.

Hwang JJ, Kuruvilla J, Mendelson D, et al. Phase I dose finding studies of obatoclax (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced solid tumors or lymphoma. Clin Cancer Res. 201016:4038–45.

Anderson MA, Huang D, Roberts A. Targeting Bcl2 for the treatment of lymphoid malignancies. Semin Hematol. 201451:219–27.

Mahmood Z, Shukla Y. Death receptors: targets for cancer therapy. Exp Cell Res. 2010316:887–99.

Bhardwaj A, Aggarwal BB. Receptor-mediated choreography of life and death. J Clin Immunol. 200323:317–32.

Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Sciences. 1998281:1305–8.

Aggarwal BB, Gupta SC, Kim JH. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood. 2012119:651–65.

Naismith JH, Sprang SR. Modularity in the TNF receptor family. Trends Biochem Sci. 199823:74–9.

Fulda S, Debatin KM. Exploiting death receptor signaling pathways for tumor therapy. Biochim Biophys Acta. 17052004:27–41.

Bremer E. Targeting of the tumor necrosis factor receptor superfamily for cancer immunotherapy. ISRN Oncol. 20132013:371854.

Walczak H, Krammer PH. The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems. Exp Cell Res. 2000256:58–66.

Behrmann I, Walczak H, Krammer PH. Structure of the human APO-1 gene. Eur J Immunol. 199424:3057–62.

Tauzin S, Debure L, Moreau JF, Legembre P. CD95-mediated cell signaling in cancer: mutations and posttranslational modulations. Cell Mol Life Sci. 201269:1261–77.

Scholl V, Stefanoff CG, Hassan R, Spector N, Renault IZ. Mutations within the 5′ region of FAS/CD95 gene in nodal diffuse large B-cell lymphoma. Leuk Lymphoma. 200748:957–63.

Ivanov VN, Ronai Z, Hei TK. Opposite roles of FAP-1 and dynamin in the regulation of Fas (CD95) translocation to the cell surface and susceptibility to Fas ligand-mediated apoptosis. J Biol Chem. 2006281:1840–52.

Tourneur L, Mistou S, Michiels FM, et al. Loss of FADD protein expression results in a biased Fas-signaling pathway and correlates with the development of tumoral status in thyroid follicular cells. Oncogene. 200322:2795–280.

Fulda S, Kufer MU, Meyer E, van Valen F, Dockhorn-Dworniczak B, Debatin KM. Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer. Oncogene. 200120:5865–77.

Yang T, Shi R, Chang L, et al. Huachansu suppresses human bladder cancer cell growth through the Fas/Fasl and TNF-alpha/TNFR1 pathway in vitro and in vivo. J Exp Clin Cancer Res. 201534:1–10.

Zhong W, Qin S, Zhu B, et al. Oxysterol-binding protein-related protein 8 [ORP8] increases sensitivity of hepatocellular carcinoma cells to Fas-mediated apoptosis. J Biol Chem. 2015290:8876–87.

Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem. 1996271:12687–90.

Mahalingam D, Szegezdi E, Keane M, de Jong S, Samali A. TRAIL receptor signalling and modulation: are we on the right TRAIL? Cancer Treat Rev. 200935:280–8.

Wu GS. TRAIL as a target in anti-cancer therapy. Cancer Lett. 2009285:1–5.

O’Leary L, van der Sloot AM, Reis CR, et al. Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity. Oncogene. 2015. doi:10.1038/onc.2015.180.

Woo JK, Kang JH, Jang YS, et al. Evaluation of preventive and therapeutic activity of novel non-steroidal anti-inflammatory drug, CG100649, in colon cancer: increased expression of TNF-related apoptosis-inducing ligand receptors enhance the apoptotic response to combination treatment with TRAIL. Oncol Rep. 20153:1947–55.

Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 1998273:14363–7.

Weichhaus M, Chung ST, Connelly L. Osteoprotegerin in breast cancer: beyond bone remodeling. Mol Cancer. 201514:117.

Lane D, Matte I, Rancourt C, Piché A. Osteoprotegerin [OPG] protects ovarian cancer cells from TRAIL-induced apoptosis but does not contribute to malignant ascites-mediated attenuation of TRAIL-induced apoptosis. J Ovarian Res. 20125:34.

Merino D, Lalaoui N, Morizot A, Solary E, Micheau O. TRAIL in cancer therapy: present and future challenges. Expert Opin Ther Targets. 200711:1299–314.

Gong B, Almasan A. Genomic organization and transcriptional regulation of human APO2/TRAIL gene. Biochem Biophys Res Commun. 2000278:747–52.

Krieg A, Krieg T, Wenzel M, et al. TRAIL-beta and TRAIL-gamma: two novel splice variants of the human TNF-related apoptosis- inducing ligand (TRAIL) without apoptotic potential. Br J Cancer. 200388:918–27.

Pal R, Gochhait S, Chattopadhyay S, et al. Functional implication of TRAIL-716 C/T promoter polymorphism on its in vitro and in vivo expression and the susceptibility to sporadic breast tumor. Breast Cancer Res Treat. 2012126:333–43.

Bos PD, Zhang XHF, Nadal C, et al. Genes that mediate breast cancer metastasis to the brain. Nature. 2009459:1005–9.

Allen JE, El-Deiry WS. Regulation of the human TRAIL gene. Cancer Biol Ther. 201213:1143–51.

Lim B, Allen JE, Prabhu VV, Talekar MK, Finnberg NK, El-Deiry WS. Targeting TRAIL in the treatment of cancer: new developments. Expert Opin Ther Targets. 201525:1–15.

Falvo JV, Tsytsykova AV, Goldfeld AE. Transcriptional control of the TNF gene. Curr Dir Autoimmun. 201011:27–60.

Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling. Cell Death Differ. 200310:45–65.

Sedger LM, McDermott MF. TNF and TNF-receptors: from mediators of cell death and inflammation to therapeutic giants—past, present and future. Cytokine Growth Factor Rev. 201425:453–72.

Wachter T, Sprick M, Hausmann D, et al. cFLIPL inhibits tumor necrosis factor-related apoptosis-inducing ligand-mediated NF-kappaB activation at the death-inducing signaling complex in human keratinocytes. J Biol Chem. 2004279:52824–34.

Ebach DR, Riehl TE, Stenson WF. Opposing effects of tumor necrosis factor receptor 1 and 2 in sepsis due to cecal ligation and puncture. Shock. 200523:311–8.

Yun HM, Park KR, Kim EC, Han SB, Yoon do Y, Hong JT. IL-32α suppresses colorectal cancer development via TNFR1-mediated death signaling. Oncotarget. 20156:9061–72.

Yu S, Hou D, Chen P, et al. Adenosine induces apoptosis through TNFR1/RIPK1/P38 axis in colon cancer cells. Biochem Biophys Res Commun. 2015460:759–65.

Bake V, Roesler S, Eckhardt I, Belz K, Fulda S. Synergistic interaction of SMAC mimetic and IFNα to trigger apoptosis in acute myeloid leukemia cells. Cancer Lett. 2014355:224–31.

Tao YF, Lu J, Du XJ, et al. Survivin selective inhibitor YM155 induce apoptosis in SK-NEP-1 Wilms tumor cells. BMC Cancer. 201226(12):619.

Ruddle NH. Lymphotoxin and TNF: how it all began—a tribute to the travelers. Cytokine Growth Factor Rev. 201425:83–9.

Chaturvedi MM, LaPushin R, Aggarwal BB. Tumor necrosis factor and lymphotoxin. Qualitative and quantitative differences in the mediation of early and late cellular response. J Biol Chem. 1994269:14575–83.

Etemadi N, Holien JK, Chau D, et al. Lymphotoxin α induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor. FEBS J. 2013280:5283–97.

de Oliveira JG, Rossi AF, Nizato DM, et al. Influence of functional polymorphisms in TNF-α, IL-8, and IL-10 cytokine genes on mRNA expression levels and risk of gastric cancer. Tumour Biol. 2015 (Epub ahead of print).

Kang YJ, Kim WJ, Bae HU, et al. Involvement of TL1A and DR3 in induction of proinflammatory cytokines and matrix metalloproteinase-9 in atherogenesis. Cytokine. 200529:229–35.

Lee SY, Debnath T, Kim SK, Lim BO. Anti-cancer effect and apoptosis induction of cordycepin through DR3 pathway in the human colonic cancer cell HT-29. Food Chem Toxicol. 201360:439–47.

Oh SB, Hwang CJ, Song SY, et al. Anti-cancer effect of tectochrysin in NSCLC cells through overexpression of death receptor and inactivation of STAT3. Cancer Lett. 2014353:95–103.

Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 20099:749–58.

Surget S, Khoury MP, Bourdon J. Uncovering the role of p53 splice variants in human malignancy: a clinical perspective. Onco Targets Ther. 20137:57–68.

Mollereau B, Ma D. The p53 control of apoptosis and proliferation: lessons from Drosophila. Apoptosis. 201419:1421–9.

Pflaum J, Schlosser S, Müller M. p53 family and cellular stress responses in cancer. Front Oncol. 20144:285.

Beckerman R, Prives C. Transcriptional regulation by p53. Cold Spring Harb Perspect Biol. 20102:a000935.

Chi SW. Structural insights into the transcription-independent apoptotic pathway of p53. BMB Rep. 201447:167–72.

Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis—the p53 network. J Cell Sci. 2003116:4077–85.

Perry ME. The regulation of the p53-mediated stress response by MDM2 and MDM4. Cold Spring Harb Perspect Biol. 20102:a000968.

Riley MF, You MJ, Multani AS, Lozano G. Mdm2 overexpression and p73 loss exacerbate genomic instability and dampen apoptosis, resulting in B-cell lymphoma. Oncogene. 2015. doi:10.1038/onc.2015.88(Epubaheadofprint).

Jansson MD, Damas ND, Lees M, Jacobsen A, Lund AH. miR-339-5p regulates the p53 tumor-suppressor pathway by targeting MDM2. Oncogene. 201434:1908–18.

Yu J, Zhang L. PUMA, a potent killer with or without p53. Oncogene Suppl. 19981:S71–83.

Hikisz P, Kiliańska ZM. PUMA, a critical mediator of cell death—one decade on from its discovery. Cell Mol Biol Lett. 201217:646–69.

Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J Biol Chem. 2002277:3247–57.

MacLachlan TK, El-Deiry WS. Apoptotic threshold is lowered by p53 transactivation of caspase-6. Proc Natl Acad Sci U S A. 200299:9492–7.

Mihara M, Erster S, Zaika A, et al. p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 200311:577–90.

Ha JH, Shin JS, Yoon MK, et al. Dual-site interactions of p53 protein transactivation domain with anti-apoptotic Bcl-2 family proteins reveal a highly convergent mechanism of divergent p53 pathways. J Biol Chem. 2013288:7387–98.

Chipuk JE, Kuwana T, Bouchier-Hayes L, et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science. 2004303:1010–4.

Leu JI, Dumont P, Hafey M, Murphy ME, George DL. Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1complex. Nat Cell Biol. 20046:443–50.

Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinicaluse. Cold Spring Harb Perspect Biol. 20102:a001008.

Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer. 20099:701–13.

Saleem S, Abbasi ZA, Hameed A, Qureshi NR, Khan MA, Azhar A. Novel p53 codon 240 Ser > Thr coding region mutation in the patients of oral squamous cell carcinoma (OSCC). Tumour Biol. 201435:7945–50.

Trbusek M, Smardova J, Malcikova J, et al. Missense mutations located in structural p53 DNA-binding motifs are associated with extremely poor survival in chronic lymphocytic leukemia. J Clin Oncol. 201129:2703–8.

Wang S, Zhou M, Ouyang J, Geng Z, Wang Z. Tetraarsenictetrasulfide and arsenic trioxide exert synergistic effects on induction of apoptosis and differentiation in acute promyelocytic leukemia cells. PLoS One. 201510:e0130343.

Gu ZT, Li L, Wu F, et al. Heat stress induced apoptosis is triggered by transcription-independent p53, Ca[2+] dyshomeostasis and the subsequent Bax mitochondrial translocation. Sci Rep. 20155:11497.

Sosin AM, Burger AM, Siddiqi A, Abrams J, Mohammad RM, Al-Katib AM. HDM2 antagonist MI-219 [spiro-oxindole], but not Nutlin-3 [cis-imidazoline], regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas. J Hematol Oncol. 20125:57.

Boeckler FM, Joerger AC, Jaggi G, Rutherford TJ, Veprintsev DB, Fersht AR. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc Natl Acad Sci U S A. 2008105:10360–5.

Vermeij R, Leffers N, van der Burg SH, Melief CJ, Daemen T, Nijman HW. Immunological and clinical effects of vaccines targeting p53-overexpressing malignancies. J Biomed Biotechnol. 20112011:702146.

Lima RT, Busacca S, Almeida GM, Gaudino G, Fennell DA, Vasconcelos MH. MicroRNA regulation of core apoptosis pathways in cancer. Eur J Cancer. 201147:163–74.

Chen Y, Fu LL, Wen X, et al. Oncogenic and tumor suppressive roles of microRNAs in apoptosis and autophagy. Apoptosis. 201419:1177–89.

Acunzo M, Visone R, Romano G, et al. Mir-130a targets MET and induces trail-sensitivity in NSCLC by downregulating mir-221 and 222. Oncogene. 201231:634–42.

Hao J, Zhang C, Zhang A, et al. miR-221/222 is the regulator of Cx43 expression in human glioblastoma cells. Oncol Rep. 201227:1504–10.

Wang P, Zhuang L, Zhang J, et al. The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL. Mol Oncol. 20137:334–45.

Qin W, Shi Y, Zhao B, et al. miR-24 regulates apoptosis by targeting the open reading frame (ORF) region of FAF1 in cancer cells. PLoS ONE. 20105:e9429.

Satzger I, Mattern A, Kuettler U, et al. microRNA-21 is upregulated in malignant melanoma and influences apoptosis of melanocytic cells. Exp Dermatol. 201221:509–14.

Eto K, Iwatsuki M, Watanabe M, et al. The microRNA-21/PTEN pathway regulates the sensitivity of HER2-positive gastric cancer cells to trastuzumab. Ann Surg Oncol. 201321:343–50.

Schickel R, Park SM, Murmann AE, Peter ME. miR-200c regulates induction of apoptosis through CD95 by targeting FAP-1. Mol Cell. 201038:908–15.

Li JH, Xiao X, Zhang YN, et al. MicroRNA miR-886-5p inhibits apoptosis by down-regulating Bax expression in human cervical carcinoma cells. Gynecol Oncol. 2011120:145–51.

Zhou M, Liu Z, Zhao Y, et al. MicroRNA-125b confers the resistance of breast cancer cells to paclitaxel through suppression of pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) expression. J Biol Chem. 2010285:21496–507.

Zhang H, Zuo Z, Lu X, Wang L, Wang H, Zhu Z. MiR-25 regulates apoptosis by targeting Bim in human ovarian cancer. Oncol Rep. 201227:594–8.

Gocek E, Wang X, Liu X, Liu CG, Studzinski GP. MicroRNA-32 upregulation by 1,25-dihydroxyvitamin D3 in human myeloid leukemia cells leads to Bim targeting and inhibition of AraC-induced apoptosis. Cancer Res. 201171:6230–9.

Veronese A, Lupini L, Consiglio J, et al. Oncogenic role of miR-483-3p at the IGF2/483 locus. Cancer Res. 201070:3140–9.

Tanaka N, Toyooka S, Soh J, et al. Downregulation of microRNA-34 induces cell proliferation and invasion of human mesothelial cells. Oncol Rep. 201329:2169–74.

Shen J, Wan R, Hu G, et al. miR-15b and miR-16 induce the apoptosis of rat activated pancreatic stellate cells by targeting Bcl-2 in vitro. Pancreatology. 201212:91–9.

Xu J, Liao X, Wong C. Downregulations of B-cell lymphoma 2 and myeloid cell leukemia sequence 1 by microRNA 153 induce apoptosis in a glioblastoma cell line DBTRG-05MG. Int J Cancer. 2010126:1029–35.

Nakano H, Miyazawa T, Kinoshita K, Yamada Y, Yoshida T. Functional screening identifies a microRNA, miR-491 that induces apoptosis by targeting Bcl-X(L) in colorectal cancer cells. Int J Cancer. 2010127:1072–80.

Shang J, Yang F, Wang Y, et al. Sun S MicroRNA-23a antisense enhances 5-fluorouracil chemosensitivity through APAF-1/caspase-9 apoptotic pathway in colorectal cancer cells. J Cell Biochem. 2014115:772–84.

Walker JC, Harland RM. MicroRNA-24a is required to repress apoptosis in the developing neural retina. Genes Dev. 200923:1046–51.

Wu JH, Yao YL, Gu T, et al. MiR-421 regulates apoptosis of BGC-823 gastric cancer cells by targeting caspase-3. Asian Pac J Cancer Prev. 201415:5463–8.

Hudson RS, Yi M, Esposito D, et al. Microrna-106b-25 cluster expression is associated with early disease recurrence and targets caspase-7 and focal adhesion in human prostate cancer. Oncogene. 201332:4139–47.

Floyd DH, Zhang Y, Dey BK, et al. Novel anti-apoptotic microRNAs 582–5p and 363 promote human glioblastoma stem cell survival via direct inhibition of caspase 3, caspase 9, and Bim. PLoS One. 20149:e96239.

Tsang WP, Kwok TT. Let-7a microRNA suppresses therapeutics-induced cancer cell death by targeting caspase-3. Apoptosis. 200813:1215–22.

Zhang J, Du Y, Wu C, et al. Curcumin promotes apoptosis in human lung adenocarcinoma cells through miR-186 signaling pathway. Oncol Rep. 201024:1217–23.

Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol. 20089:139–50.

Barth BM, Cabot MC, Kester M. Ceramide-based therapeutics for the treatment of cancer. Anti Cancer Agents Med Chem. 201111:911–9.

Senchenkov A, Litvak DA, Cabot MC. Targeting ceramide metabolism—a strategy for overcoming drug resistance. J Natl Cancer Inst. 200193:347–57.

Siskind LJ, Kolesnick RN, Colombini M. Ceramide channels increase the permeability of the mitochondrial outer membrane to small proteins. J Biol Chem. 2002277:26796–803.

Siskind LJ, Feinstein L, Yu TX, et al. Anti-apoptotic Bcl-2 family proteins disassemble ceramide channels. J Biol Chem. 2008283:6622–30.

von Haefen C, Wieder T, Gillissen B, et al. Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells. Oncogene. 200221:4009–19.

Dumitru CA, Sandalcioglu IE, Wagner M, Weller M, Gulbins E. Lysosomal ceramide mediates gemcitabine-induced death of glioma cells. J Mol Med. 200987:1123–32.

Ogretmen B, Hannun YA. Biologically active sphingolipids in cancer: pathogenesis and treatment. Nat Rev Cancer. 20044:604–16.

Liu F, Verin AD, Wang P, et al. Differential regulation of sphingosine-1-phosphate- and VEGF-induced endothelial cell chemotaxis. Involvement of G(ialpha2)-linked Rho kinase activity. Am J Respir Cell Mol Biol. 200124:711–9.

Radin NS. The development of aggressive cancer: a possible role for sphingolipids. Cancer Investig. 200220:779–86.

Pchejetski D, Golzio M, Bonhoure E, et al. Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models. Cancer Res. 200565:11667–75.

Beckham TH, Lu P, Jones EE, et al. LCL124, a cationic analog of ceramide, selectively induces pancreatic cancer cell death by accumulating in mitochondria. J Pharmacol Exp Ther. 2013344(1):167–78.

Jiang Y, DiVittore NA, Kaiser JM, et al. Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer. Cancer Biol Ther. 201112(7):574–85.

Sorli SC, Colié S, Albinet V, et al. The nonlysosomal β-glucosidase GBA2 promotes endoplasmic reticulum stress and impairs tumorigenicity of human melanoma cells. FASEB J. 201327(2):489–98.

Stover TC, Sharma A, Robertson GP, Kester M. Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. Clin Cancer Res. 200511(9):3465–74.

Beljanski V, Lewis CS, Smith CD. Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts. Cancer Biol Ther. 201111(5):524–34.

Adan-Gokbulut A, Kartal-Yandim M, Iskender G, Baran Y. Novel agents targeting bioactive sphingolipids for the treatment of cancer. Curr Med Chem. 201320(1):108–22.

Coward J, Ambrosini G, Musi E, Truman JP, Haimovitz-Friedman A, Allegood JC. Safingol (L-threo-sphinganine) induces autophagy in solid tumor cells through inhibition of PKC and the PI3-kinase pathway. Autophagy. 20095:184–93.

Pyne S, Bittman R, Pyne NJ. Sphingosine kinase inhibitors and cancer: seeking the golden sword of Hercules. Cancer Res. 201171(21):6576–82.

Taouji S, Higa A, Delom F, et al. Phosphorylation of serine palmitoyltransferase long chain-1 (SPTLC1) on tyrosine 164 inhibits its activity and promotes cell survival. J Biol Chem. 2013288(24):17190–201.

Huang WC, Tsai CC, Chen CL, et al. Glucosylceramide synthase inhibitor PDMP sensitizes chronic myeloid leukemia T315I mutant to Bcr-Abl inhibitor and cooperatively induces glycogen synthase kinase-3-regulated apoptosis. FASEB J. 201125(10):3661–73.

Nica AF, Tsao CC, Watt JC, et al. Ceramide promotes apoptosis in chronic myelogenous leukemia-derived K562 cells by a mechanism involving caspase-8 and JNK. Cell Cycle. 20087(21):3362–70.

Camgoz A, Gencer EB, Ural AU, Baran Y. Mechanisms responsible for nilotinib resistance in human chronic myeloid leukemia cells and reversal of resistance. Leukemia Lymphoma. 201354:1279–87.

Baran Y, Bielawski J, Gunduz U, Ogretmen B. Targeting glucosylceramide synthase sensitizes imatinib-resistant chronic myeloid leukemia cells via endogenous ceramide accumulation. J Cancer Res Clin Oncol. 2011137:1535–44.

Kartal M, Saydam G, Sahin F, Baran Y. Resveratrol triggers apoptosis through regulating ceramide metabolizing genes in human K562 chronic myeloid leukemia cells. Nutr Cancer. 201163(4):637–44.

Cakir Z, Saydam G, Sahin F, Baran Y. The roles of bioactive sphingolipids in resveratrol-induced apoptosis in HL60: acute myeloid leukemia cells. J Cancer Res Clin Oncol. 2011137(2):279–86.

Camgoz A, Gencer EB, Ural AU, Avcu F, Baran Y. Roles of ceramide synthase and ceramide clearence genes in nilotinib-induced cell death in chronic myeloid leukemia cells. Leukemia Lymphoma. 201152:1574–84.

Gencer EB, Ural AU, Avcu F, Baran Y. A novel mechanism of dasatinib-induced apoptosis in chronic myeloid leukemia ceramide synthase and ceramide clearance genes. Ann Hematol. 201190:1265–75.


Americas

Site will be displayed in English.

We use these cookies to ensure our site functions securely and properly they are necessary for our services to function and cannot be switched off in our systems. They are usually only set in response to actions made by you which amount to a request for services, such as logging in, using a shopping cart or filling in forms. You can set your browser to block or alert you about these cookies, but some parts of our services will not work without them. Like the other cookies we use, strictly necessary cookies may be either first-party cookies or third - party cookies.

We use these cookies to remember your settings and preferences. For example, we may use these cookies to remember your language preferences.
Allow Preference Cookies

We use these cookies to collect information about how you interact with our services and to help us measure and improve them. For example, we may use these cookies to determine if you have interacted with a certain page.
Allow Performance/Statistics Cookies

We and our advertising partners use these cookies to deliver advertisements, to make them more relevant and meaningful to you, and to track the efficiency of our advertising campaigns, both on our services and on other websites and social media.
Allow Marketing Cookies


Reciprocal Spatiotemporally Controlled apoptosis Regulates Wolffian Duct Cloaca Fusion ⎗]

"The epithelial Wolffian duct (WD) inserts into the cloaca (primitive bladder) before metanephric kidney development, thereby establishing the initial plumbing for eventual joining of the ureters and bladder. Defects in this process cause common anomalies in the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). However, developmental, cellular, and molecular mechanisms of WD-cloaca fusion are poorly understood. Through systematic analysis of early WD tip development in mice, we discovered that a novel process of spatiotemporally regulated apoptosis in WD and cloaca was necessary for WD-cloaca fusion. Aberrant RET tyrosine kinase signaling through tyrosine (Y) 1062, to which PI3K- or ERK-activating proteins dock, or Y1015, to which PLCγ docks, has been shown to cause CAKUT-like defects. Cloacal apoptosis did not occur in RetY1062F mutants, in which WDs did not reach the cloaca, or in RetY1015F mutants, in which WD tips reached the cloaca but did not fuse. Moreover, inhibition of ERK or apoptosis prevented WD-cloaca fusion in cultures, and WD-specific genetic deletion of YAP attenuated cloacal apoptosis and WD-cloacal fusion in vivo Thus, cloacal apoptosis requires direct contact and signals from the WD tip and is necessary for WD-cloacal fusion. These findings may explain the mechanisms of many CAKUT." Links: genital | testis


The interaction mechanism between autophagy and apoptosis in colon cancer

Autophagy and apoptosis play crucial roles in tumorigenesis. Recent studies have shown that autophagy and apoptosis have a cross-talk relationship in anti-tumor therapy. It is well established that apoptosis is one of the main pathways of tumor cell death. While autophagy can occurs in tumors with opposite function: protective autophagy and lethal autophagy. Protective autophagy can inhibit tumor apoptosis induced by anticancer drugs, while lethal autophagy can induce tumor cell apoptosis in cooperation with anticancer drugs. Hence, autophagy and apoptosis have synergistic and antagonistic effects in tumor. Colorectal cancer is a common malignant tumor with high morbidity and mortality. In recent years, colorectal carcinoma has achieved improved clinical efficacy with drug treatment. Nonetheless, increasing drug-resistance limit the treatment efficacy, highlighting the urgency of exploring the molecular events that drive drug resistance. Researchers have found that autophagy is one of the major factors leading to drug resistance in colon cancer. Therefore, elucidating the interaction between autophagy and apoptosis is helpful to improve the efficacy of anticancer drugs in clinical treatment of colorectal cancer. This review attaches great importance to the relationship between autophagy and apoptosis and related factors in colorectal cancer.


Cell Signaling and Cellular Metabolism

The rush of adrenaline that leads to greater glucose availability is an example of an increase in metabolism.

Learning Objectives

Explain how cellular metabolism can be altered

Key Takeaways

Key Points

  • The activation of β-adrenergic receptors in muscle cells by adrenaline leads to an increase in cyclic AMP.
  • Cyclic AMP activates PKA (protein kinase A), which phosphorylates two enzymes.
  • Phophorylation of the first enzyme promotes the degradation of glycogen by activating intermediate GPK that in turn activates GP, which catabolizes glycogen into glucose.
  • Phosphorylation of the second enzyme, glycogen synthase (GS), inhibits its ability to form glycogen from glucose.
  • The inhibition of glucose to form glycogen prevents a futile cycle of glycogen degradation and synthesis, so glucose is then available for use by the muscle cell.

Key Terms

  • cyclic adenosine monophosphate: cAMP, a second messenger derived from ATP that is involved in the activation of protein kinases and regulates the effects of adrenaline
  • epinephrine: (adrenaline) an amino acid-derived hormone secreted by the adrenal gland in response to stress
  • protein kinase A: a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP)

Increase in Cellular Metabolism

As the environments of most organisms are constantly changing, the reactions of metabolism must be finely regulated to maintain a constant set of conditions within cells. Metabolic regulation also allows organisms to respond to signals and interact actively with their environments. Two closely-linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the regulation of an enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, the control exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway. For example, an enzyme may show large changes in activity (i.e. it is highly regulated), but if these changes have little effect on the rate of a metabolic pathway, then this enzyme is not involved in the control of the pathway.

The result of one such signaling pathway affects muscle cells and is a good example of an increase in cellular metabolism. The activation of β-adrenergic receptors in muscle cells by adrenaline leads to an increase in cyclic adenosine monophosphate (also known as cyclic AMP or cAMP) inside the cell. Also known as epinephrine, adrenaline is a hormone (produced by the adrenal gland attached to the kidney) that prepares the body for short-term emergencies. Cyclic AMP activates PKA (protein kinase A), which in turn phosphorylates two enzymes. The first enzyme promotes the degradation of glycogen by activating intermediate glycogen phosphorylase kinase (GPK) that in turn activates glycogen phosphorylase (GP), which catabolizes glycogen into glucose. (Recall that your body converts excess glucose to glycogen for short-term storage. When energy is needed, glycogen is quickly reconverted to glucose. ) Phosphorylation of the second enzyme, glycogen synthase (GS), inhibits its ability to form glycogen from glucose. In this manner, a muscle cell obtains a ready pool of glucose by activating its formation via glycogen degradation and by inhibiting the use of glucose to form glycogen, thus preventing a futile cycle of glycogen degradation and synthesis. The glucose is then available for use by the muscle cell in response to a sudden surge of adrenaline—the “fight or flight” reflex.

Formation of Cyclic AMP: This diagram shows the mechanism for the formation of cyclic AMP (cAMP). cAMP serves as a second messenger to activate or inactivate proteins within the cell.


In what ways can mechanisms of apoptosis be damaged? - Biology

Article Summary:

Apoptosis:-
Apoptosis is the programmed cell death in which cells before dying undergo series of events. Through this way, the unnecessary cells are removed from the body or the cells which cause harm to the body. Apoptosis usually occurs during the embryonic stages when the cells are growing and developing. It can also occur in adult cells which are affected through some injury or when the tissues need to be remodeled. Aging is another factor which causes apoptosis. Process of apoptosis is also celled as cell suicide because cells use cellular machinery to kill themselves. It takes place only in multicellular organisms. It is a normal thing when the cell functions and if there is an incomplete process of apoptosis it may lead to the development of malignant and benign tumors.

What Triggers the Process of Apoptosis:-
For every process which occurs in the body, there is some reason behind it. There are numerous causes which make the process of apoptosis to take place. The most important cause is the DNA damage. When the body of the person is exposed to ionizing radiations like x-rays, ultraviolet radiations or chemotherapy medications for the treatment of cancer then apoptosis can occur. Another factor which triggers apoptosis is the corticosteroids. On the surface of the every cell there is a special type of protein called as Fas protein, it also causes the cell suicide.

How Apoptosis Takes Place:-

There are several steps involved in the programmed cell death

1) When the unnecessary enzymes start activating in the cell, they eat up the proteins due to which cell starts becoming round.

2) DNA present inside the nucleus starts separating and eventually it shrinks down.

3) There is a nuclear membrane around the nucleus, when the apoptosis starts, it degrades and cell's nucleus becomes without the outer layer.

4) Due to the absence of the nuclear membrane, the DNA molecule starts rupturing into small fragments. These fragments are not in a particular size.

5) As nucleus is no longer protected that is why it breaks down into many pieces along with the uneven pieces of DNA molecule.

6) Due to the breakage inside the cell, cell itself starts degrading through the process of blebbing.

7) Blebbing converts the cell into mall pieces which are eaten by other small cells known as phagocytes.

There are three types of apoptosis

Internal Apoptosis:-
Apoptosis can occur through internal signals. Internal signals mean when there is damage to the cell internally. Internal damage triggers a protein called BAX. This protein pricks the mitochondrial membrane. Mitochondria are the power house of the cell and they provide energy to the cell to perform various functions. Due to the puncturing of mitochondrial wall, cytochrome c releases from it and binds to the Apaf-1. This binding makes the production of apoptosomes which trigger apoptosis. These apoptosomes cause the formation of capsases. Capsases breakdown the structure of the cell and DNA destroys ultimately.

External Apoptosis:-
External signals also cause the apoptosis to occur. The Fas proteins on the surface of the cell bind to another protein called TNF or tumor necrosis factor which will in turn trigger the signal in cytoplasm and will activate capsase 8. This enzyme will lead to the formation of more capsases which will eventually breakdown the cell and destroy the DNA.

Apoptosis Inducing Factor:-
Apoptosis inducing factor also causes the cell suicide. This type of apoptosis usually occurs in the neurons which are the responsible for conducting the nerve impulses. Other cells can also undergo AIF. It is a protein present inside the mitochondrial intermembrane space. When the apoptosis starts, cell receives a signal of death and in response to this AIF is released in the cytoplasm. This protein reaches to the nucleus and destroys the DNA molecule. When DNA will be killed then there will be no activity taking place inside the cell and cell will die automatically.

About Author / Additional Info:

Important Disclaimer: All articles on this website are for general information only and is not a professional or experts advice. We do not own any responsibility for correctness or authenticity of the information presented in this article, or any loss or injury resulting from it. We do not endorse these articles, we are neither affiliated with the authors of these articles nor responsible for their content. Please see our disclaimer section for complete terms.


RELEVANCE TO CLINICAL PRACTICE

Apoptosis, necrosis, autophagy and senescence

In this section, the cell death and senescence processes will be described. Understanding of these processes contributes to insight on normal biological aging and diseases of aging.

Background: Cell damage and mitochondria 3,4,5

As noted above, normal aging is associated with increased accumulation of cellular damage. Many types of stress can cause cellular damage, including low oxygen levels, DNA alterations, low nutrient levels, and oxidative stress [exposure to increased levels of reactive oxygen species, (ROS)]. Damage from these stressors can include DNA mutations, protein unfolding, and oxidation of lipids in membranes, all of which can impair cellular function. Because mitochondria are sites of high ROS production, they are key organelles in the aging process. Mitochondria also are important organelles in the induction of apoptosis, autophagy and senescence.

Apoptosis is the process of programmed cell death. In this process, damaged cells self-destruct, and are removed by phagocytosis without triggering inflammation. Apoptosis can occur via a number of intracellular signaling pathways ROS-modified molecules can serve as triggers and/or apoptotic signaling molecules. The apoptosis pathways are strongly regulated, with intricate interplay between anti-apoptotic and pro-apoptotic factors.

Apoptosis is a vital process in normal embryogenesis and in maturation of the immune system It also facilitates organism survival by removing damaged cells without inflammatory injury to remaining cells. Research has found that apoptosis is often decreased human aging. Much remains to be learned about the actual contribution of apoptosis to normal aging.

Necrosis is the process of cell death due to injury from trauma, infection, extreme thermal stress, or other factors.In contrast to apoptosis, necrosis activates inflammation pathways that can be harmful to surrounding cells.

Autophagy is the process by which damaged molecules, organelles or cells are degraded enzymatically. The damaged entity is surrounded by a membrane and transported to the lysosome for digestion. Amino acids and other products of the digestion are then used for cell maintenance. Autophagy may or may not result in cell death. For example, if specific damaged proteins or mitochondria are autophagically removed, the process may actually assist in cell survival rather than in cell death.

Like apoptosis, autophagy is important in normal growth and development. Autophagy also decreases with normal aging which can result in accumulation of malfunctioning proteins, mitochondria and other organelles.

Senescence is the process by which damaged cells lose their ability to divide, but without cell death or neoplastic transformation. Similar to apoptosis, senescence is an important process in embryogenesis it is also in wound healing. However, senescent cells can contribute to an unhealthy environment around them by expressing inflammatory cytokines [senescence associated secretory phenotype [SASP]. DNA damage is a common initiator of the senescence pathway. Cultured senescent cells are also typically apoptosis-resistant, but it is not known if this characteristic is manifested by cells in vivo.

Molecular markers of senescent cells have been found to be increased in many aging tissues of animal models and humans. This increase is thought to indicate increased numbers of senescent cells in aging, but confirming evidence is needed. The increase in numbers of senescent cells has been linked to the pro-inflammatory phenotype often seen with aging. Increased serum inflammatory cytokines have also been documented in human aging. The higher numbers of senescent cells may also contribute to etiologies of inflammation-related diseases of aging, such as atherosclerosis. Correlation has not yet been made between numbers of senescent cells and body-wide changes of normal aging.

Which pathway is used? 4,5,6

The relationship between apoptosis, necrosis, autophagy and senescence is variable. The process is used by a cell depends on the specific tissues and cells involved, and may also be influenced by the severity of the inciting cellular stress. Milder stress may foster autophagy or senescence, with moderate stress resulting in apoptosis, and severe stress leading to necrosis.

Tissue effects in aging

This section discusses research findings regarding the relationships between tissue changes of normal aging and the processes of apoptosis, necrosis, autophagy, and senescence. Much of the current knowledge on this topic is derived from animal models. Extensive research remains yet to be done in human cells and tissues. The reader is referred to the Biology of Aging section of PM&R Knowledge NOW for more information on general organ-related changes of normal aging.

The total number of cardiac myocytes decreases by as much as 30% with age apoptosis is the primary pathway in this decrease. The heart is not able to regenerate or replace all these lost cells, so the remaining cells tend to hypertrophy. Specific inciting factors for this apoptosis are not known, although accumulated mitochondrial gene mutations appear to contribute.

Autophagy is also important for removal of damaged mitochondria in the cardiac myocytes. Exercise has been found to increase autophagy in the myocardium, and therefore may be a mechanism by which exercise is cardioprotective.

Estrogen is anti-apoptotic for osteoblasts, and pro-apoptotic for osteoclasts. Thus age-related estrogen decline may contribute to bone loss via a shift in the balance between programmed cell death and survival of these two cell types. Although increased senescence markers have been documented in bone of older persons, not enough is known yet to make any firm conclusions about the contribution of senescence to age-related bone loss in humans.

Damaged proteins and DNA have been identified in aging human discs, as have apoptotic and senescent cells. Elevated levels of senescence markers have also been identified in aged human disc, thought to indicate increased numbers of senescent cells in older discs vs. younger ones. Further study is needed to better define specifically how apoptosis and senescence relate to functional changes in aging disc tissue.

Skeletal Muscle 16,17,18,19,20

Sarcopenia is the age-related decrease of muscle mass and muscle function, characterized by muscle atrophy and decreased myofiber number. A full understanding has yet to be reached regarding the etiologic complexities of this condition. However, it has been reported that there is a decrease in skeletal muscle autophagy with aging, particularly in autophagy for damaged mitochondria (mitophagy). There is also an increase is apoptosis. This alteration in balance between muscle repair and cell death promotes accumulation of damaged mitochondria and associated increased release of ROS, as well as decreased clearance of ROS-mediated cellular injury. There is very little experimental data to date regarding cellular senescence in aging skeletal muscle.

In muscles of aged experimental animals, aerobic exercise has been found to decrease components of apoptotic pathways, and increase components of autophagy pathways as well as to mitigate muscle atrophy. Chronic training also has been found to decrease ROS production in skeletal muscle, a decrease in oxidative stress. This oxidative stress reduction may decrease muscle apoptosis however, more study is needed here.

Nervous system 17,19,21,22,23

Structural mitochondrial abnormalities have been documented in pre-synaptic axons of aged mice. DNA damage and ROS-mediated mitochondrial dysfunction have also been documented in aging alpha motor neurons such stressors can lead to apoptotic demise of these neurons. This motor nerve loss contributes to the muscle atrophy and decreased muscle cell number of sarcopenia Additionally, mitophagy is decreased in aging motor neurons, which may also contribute to alpha motor neuron loss due to accumulation of damaged organelles and proteins. Data is quite limited regarding the presence or functional significance of senescent cells in aging CNS.

In aging, there is an increase in lymphocyte apoptosis,which is thought to contribute to a decreased number of T lymphocytes.Accumulation of senescent lymphocytes may contribute to a pro-inflammatory state in aging.


Mechanisms of natural killer cell-mediated cellular cytotoxicity

Cellular cytotoxicity, the ability to kill other cells, is an important effector mechanism of the immune system to combat viral infections and cancer. Cytotoxic T cells and natural killer (NK) cells are the major mediators of this activity. Here, we summarize the cytotoxic mechanisms of NK cells. NK cells can kill virally infected of transformed cells via the directed release of lytic granules or by inducing death receptor-mediated apoptosis via the expression of Fas ligand or TRAIL. The biogenesis of perforin and granzymes, the major components of lytic granules, is a highly regulated process to prevent damage during the synthesis of these cytotoxic molecules. Additionally, NK cells have developed several strategies to protect themselves from the cytotoxic activity of granular content upon degranulation. While granule-mediated apoptosis is a fast process, death receptor-mediated cytotoxicity requires more time. Current data suggest that these 2 cytotoxic mechanisms are regulated during the serial killing activity of NK cells. As many modern approaches of cancer immunotherapy rely on cellular cytotoxicity for their effectiveness, unraveling these pathways will be important to further progress these therapeutic strategies.

Keywords: apoptosis death receptors degranulation granzyme perforin.


Watch the video: From DNA to protein - 3D (August 2022).