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Article Evaluation

Article: Chromosome Abnormality

After reading this article, everything on this page is relevant to the topic chromosome abnormality, however there were some distractions making it hard to read. Some of the ideas don't completely finish before jumping onto the next point. For example, in the introduction, the article was talking about the definition of chromosome abnormality and then jumped right to the definition of a karyotype, which wasn't necessarily even needed in the introduction. All of the claims or facts were neutral with none being heavily biased towards a particular position. Since this was a fairly short article, nothing was overrepresent, however I felt that there was a lot of information underrepresented. For example, the method of actually getting an aneuploidy either through mitosis or meiosis could have been covered as this is known (what leads to trisomies and monosomies). Another example is when the article talks about acquired chromosomal abnormalities, this section was very brief and more information could have been added such as what sparks these abnormalities and can you get them from other mutations. Furthermore, a heavily underrepresented topic was that chromosome abnormalities can cause diseases, although it was mentioned I think that the result of chromosomal abnormalities should have a larger impact on this article. In terms of citations, all the links work, however I found that a lot of the cited information was copied word for word from the source, for example with cite 11. In addition, not all of the facts were cited, whole subsections of the topic such as how to detect abnormalities and inheritance were not cited. Furthermore, some of the information doesn't seem to come from a credible source, a lot was taken from the same source which was a website seemingly made by some professors, however this information on this website should have been cited from somewhere. Not a lot of information seems to be out of date, however I think new technology or ways to detect chromosomal abnormalities have recently been discovered or used which could be added. I think there should also be more information about the many types of popular chromosomal diseases resulting from chromosomal abnormalities added to this article. On this article's Talk page there are conversations or suggestions about adding more recently discovered types of chromosomal abnormalities and a proposition about adding more tables to the article. This article was rated as a start and Wikipedia discusses this article very generically covering the very basics of chromosome abnormality. In class and previous courses, we've talked more in depth about chromosomal abnormality again showing how it occurs and the results of these abnormalities.

Possible topics

Article : https://en.wikipedia.org/w/index.php?title=Caspase%2D%39 Caspase-9

I can add a lot more information such as what it's purpose is, etc. I can also add the damaging effects that might occur if this doesn't work or get activated.

Article: Wild type

I can improve this article by using the correct terms to explain what wild type is and include more examples of wild types commonly used in research.

Draft Article

Caspase-9

[edit]

Caspase-9 is an enzyme encoded by the CASP9 gene in humans.[1] It is an initiator caspase, responsible for initiating the intrinsic apoptosis pathway (mitochondrial apoptosis).[2] Caspase-9 belongs to the family of caspases, cysteine-aspartic acid proteases involved in apoptosis & cytokine signalling.[3]

Correct caspase-9 function is required for apoptosis, leading to the normal development of the central nervous system.[3] Without correct function, abnormal development of tissues can occur leading to diseases and premature death.[3] Certain diseases involving caspase-9 are treated with therapy by targeting this enzyme.[3]

Different protein isoforms of caspase-9 are produced due alternative splicing.[4]

Structure

[edit]

Similar with other caspases, caspase-9 has 3 domains: N-terminal pro-domain, large subunit, and small subunit.[3] The N-terminal pro-domain is also called the long pro-domain and this contains the caspase activation domain (CARD) motif.[5]

The caspase-9 monomer consists of one large and one small subunit, both comprising the catalytic domain.[6] Differing from the normally conserved active site motif QACRG in other caspases, caspase-9 has the motif QACGG.[7][8]

When dimerized, caspase-9 has two different active site conformations within each dimer.[6] One site closely resembles the catalytic sites of other caspases, whereas in the second, there is no present "activation loop", disrupting the catalytic machinery in that particular active site.[6] The active catalytic site has broad substrate specificity because of a wide substrate-binding cleft.[9]

The caspase-9 dimer is asymmetrical

Localization

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Caspase-9 is found in the mitochondria, cytosol, and nucleus.[10]

Expression

[edit]

Caspase-9 in humans is expressed in fetus and adult tissues. [7][8] Tissue expression of caspase-9 is ubiquitous with the highest expression in the heart, specifically in its muscle cells.[11] The liver, pancreas, and skeletal muscle express this enzyme at moderate levels, and all other tissues express caspase-9 at lower levels.[11]

Mechanism

[edit]

Active caspase-9 acts as an executioner pathway, initiating apoptosis[12]

  • Activated caspase-9 then cleaves further caspases, initiating the caspase cascade (thus initiating apoptosis)[3]

When inactive, caspase-9 is in the cytosol of a cell as a monomer (zymogen) [12][6]

  • It is recruited and activated by the CARDs (caspase recruitment domain motif) in the APAF1 oligomeric complex[13]

Processing

[edit]
  • Before activation, caspase-9 has to be processed [14]
    • It has to be processed because caspase-9 is first made as single-chain zymogens which are inactive[14]
      • Further processed into its large & small subunits[6]
    • In order to start apoptosis, Apaf-1 helps the autoproteolytic processing of the single-chain caspsase-9 zymogen [14]
    • Processing occurs when the apoptosome binds to caspase-9 zymogen the processed caspase-9 stays bound to the apoptosome forming a holoenzyme [15]

Activation

[edit]

Two different ways for activation:

  1. Activated when binding to APAF1 (through apoptotic signal), it dimerizes[2] - activated by the apoptosome[14]
  • Apaf1 oligomerizes pro-caspase-9's precursor molecules for auto activation of caspase-9[16]

2. Activated by proteolytic cleavage by a previously activated caspase, which then dimerizes caspase-9[17]

Catalytic Activity

[edit]
  • Asp at position P1 (strict) & marked preference for His at position P2[18]    
  • Preferred cleavage sequence of Leu-Gly-His-Asp-(cut) Xaa[18]    

Regulation

[edit]
  • Regulation of caspase-9 occurs through phosphorylation
    • Negative regulation [3]
  • Through Akt, a serine-threonine kinase phosphorylates caspase-9 on serine-196 which inhibits its activation and protease activity, thus suppressing caspase-9 & further apoptosis [19]
    • Akt can phosphorylate both processed & unprocessed caspase-9 in-vitro[20]
      • On processed, it phosphorylates on large subunit in vitro[20]
    • Since the phosphorylated serine is far from the substrate-binding site of caspase-9, this means that caspase-9 is allosterically inhibited[21][20]
      • Inhibition may affect the way caspase-9 dimerizes and it may alter the substrate-cleft/active site of caspase-9 through conformational changes [20]

Mutations/Deficiency

[edit]
  • When you have a deficiency in caspase-9 it can affect the development of the brain [22]
    • Ex. Caspase-9 deficient mice have large brains as a result of decreased apoptosis and an increase in extra neurons [23]
      • Also, when homozygous for no caspase-9, in mice, they usually die perinatally due to a an abnormally developed cerebrum [3]
      • The effects of being caspase-9 deficient or a mutant is detrimental compared to mutants of other caspase [3]
        • This may demonstrate that caspase-9 plays a very important role in apoptosis as it is responsible for further activation of other caspases [3]
      • Caspase-9 deficient mice have a main phenotype showing an impact on the brain [3]
        • This could mean that caspase-9 could play a role in the pathway of many disease that are associated with the brain such as a stroke, hypoxia, or neurodevelopment disorders [3]

Clinical Significance

[edit]
  • Expression of caspase-9 is found at different levels among different tissues in the human body[24]
    • Different levels of caspase-9 have a physiological role[24]
    • Too low amount of caspase-9 results in neurodegenerative diseases & malignancies[24]
      • Alzheimer's disease is a result of low expression of caspase-9[25]
  • Mutations in the caspase-9 gene can also cause diseases[12]
    • Germline variation is linked to non-Hodgkin's lymphoma [26]
      • Alteration at both gene & SNP levels of caspase-9 have been associated with this disease risk [26]
  • Caspase-9 can also affect a person's risk of lung cancer
    • Certain polymorphisms in the caspase-9 promoter give rise to a higher chance of lung cancer due to an increase promoter activity which enhances caspase-9 activity/expression [27]
  • However, the induction of caspases may have medical benefits[12]
    • It can be used to eliminate lymphocytes in graft versus host disease by having a modified version of a caspase-9 that you can turn on & off where in the presence of a small molecule it will dimerize & activate its hydrolyzing domain which will trigger apoptosis[28]

Alternative Transcripts

[edit]

Through alternative splicing, four different caspase-9 variants are produced.

Caspase-9α (9L)

[edit]

This variant is used as the reference sequence, and it has full cysteine protease activity.[29][5] (insert picture of reference sequence)

Caspase-9β (9S)

[edit]

This variant doesn't include exons 3, 4, 5, and 6; it is missing amino acids 140-289.[5][29] Caspase-9S doesn't have central catalytic domain, therefore it functions as an inhibitor of caspase-9α by attaching to the apoptosome, suppressing the caspase enzyme cascade and apoptosis.[5][30] Caspase-9β is referred to as the endogenous dominant-negative isoform.

Caspase-9γ

[edit]

This variant is missing amino acids 155-416, and for amino acids 152-154, the sequence AYI is changed to TVL.[29]

Isoform 4

[edit]

In comparison with the reference sequence, it is missing amino acids 1-83.[29]

  1. ^ Li, Peng; Nijhawan, Deepak; Budihardjo, Imawati; Srinivasula, Srinivasa M; Ahmad, Manzoor; Alnemri, Emad S; Wang, Xiaodong (1997-11-14). "Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade". Cell. 91 (4): 479–489. doi:10.1016/S0092-8674(00)80434-1.
  2. ^ a b Shiozaki, Eric N.; Chai, Jijie; Shi, Yigong (2002-04-02). "Oligomerization and activation of caspase-9, induced by Apaf-1 CARD". Proceedings of the National Academy of Sciences. 99 (7): 4197–4202. doi:10.1073/pnas.072544399. ISSN 0027-8424. PMID 11904389.
  3. ^ a b c d e f g h i j k l Kuida, Keisuke (2000-02-01). "Caspase-9". The International Journal of Biochemistry & Cell Biology. 32 (2): 121–124. doi:10.1016/S1357-2725(99)00024-2.
  4. ^ "CASP9 caspase 9 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-11-29.
  5. ^ a b c d Li, Ping; Zhou, Libin; Zhao, Ting; Liu, Xiongxiong; Zhang, Pengcheng; Liu, Yan; Zheng, Xiaogang; Li, Qiang (2017-02-04). "Caspase-9: structure, mechanisms and clinical application". Oncotarget. 8 (14): 23996–24008. doi:10.18632/oncotarget.15098. ISSN 1949-2553. PMC 5410359. PMID 28177918.{{cite journal}}: CS1 maint: PMC format (link)
  6. ^ a b c d e Renatus, Martin; Stennicke, Henning R.; Scott, Fiona L.; Liddington, Robert C.; Salvesen, Guy S. (2001-12-04). "Dimer formation drives the activation of the cell death protease caspase 9". Proceedings of the National Academy of Sciences. 98 (25): 14250–14255. doi:10.1073/pnas.231465798. ISSN 0027-8424. PMID 11734640.
  7. ^ a b Duan, H.; Orth, K.; Chinnaiyan, A. M.; Poirier, G. G.; Froelich, C. J.; He, W. W.; Dixit, V. M. (1996-07-12). "ICE-LAP6, a novel member of the ICE/Ced-3 gene family, is activated by the cytotoxic T cell protease granzyme B". The Journal of Biological Chemistry. 271 (28): 16720–16724. ISSN 0021-9258. PMID 8663294.
  8. ^ a b Srinivasula, S. M.; Fernandes-Alnemri, T.; Zangrilli, J.; Robertson, N.; Armstrong, R. C.; Wang, L.; Trapani, J. A.; Tomaselli, K. J.; Litwack, G. (1996-10-25). "The Ced-3/interleukin 1beta converting enzyme-like homolog Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator CPP32". The Journal of Biological Chemistry. 271 (43): 27099–27106. ISSN 0021-9258. PMID 8900201.
  9. ^ Thornberry, Nancy A.; Rano, Thomas A.; Peterson, Erin P.; Rasper, Dita M.; Timkey, Tracy; Garcia-Calvo, Margarita; Houtzager, Vicky M.; Nordstrom, Penny A.; Roy, Sophie (1997-07-18). "A Combinatorial Approach Defines Specificities of Members of the Caspase Family and Granzyme B FUNCTIONAL RELATIONSHIPS ESTABLISHED FOR KEY MEDIATORS OF APOPTOSIS". Journal of Biological Chemistry. 272 (29): 17907–17911. doi:10.1074/jbc.272.29.17907. ISSN 0021-9258. PMID 9218414.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ Zhivotovsky, B.; Samali, A.; Gahm, A.; Orrenius, S. (July 1999). "Caspases: their intracellular localization and translocation during apoptosis". Cell Death and Differentiation. 6 (7): 644–651. doi:10.1038/sj.cdd.4400536. ISSN 1350-9047. PMID 10453075.
  11. ^ a b Han, Yuchi; Chen, Yee-Shiuan; Liu, Zhilin; Bodyak, Natalya; Rigor, Debra; Bisping, Egbert; Pu, William T.; Kang, Peter M. (2006-08-18). "Overexpression of HAX-1 protects cardiac myocytes from apoptosis through caspase-9 inhibition". Circulation Research. 99 (4): 415–423. doi:10.1161/01.RES.0000237387.05259.a5. ISSN 1524-4571. PMID 16857965.
  12. ^ a b c d McIlwain, David R.; Berger, Thorsten; Mak, Tak W. (2013-04-01). "Caspase Functions in Cell Death and Disease". Cold Spring Harbor Perspectives in Biology. 5 (4): a008656. doi:10.1101/cshperspect.a008656. ISSN 1943-0264. PMID 23545416.
  13. ^ Acehan, Devrim; Jiang, Xuejun; Morgan, David Gene; Heuser, John E; Wang, Xiaodong; Akey, Christopher W (2002-02-01). "Three-Dimensional Structure of the Apoptosome: Implications for Assembly, Procaspase-9 Binding, and Activation". Molecular Cell. 9 (2): 423–432. doi:10.1016/S1097-2765(02)00442-2.
  14. ^ a b c d Hu, Qi; Wu, Di; Chen, Wen; Yan, Zhen; Shi, Yigong (2013-05-24). "Proteolytic Processing of the Caspase-9 Zymogen Is Required for Apoptosome-mediated Activation of Caspase-9". The Journal of Biological Chemistry. 288 (21): 15142–15147. doi:10.1074/jbc.M112.441568. ISSN 0021-9258. PMC 3663534. PMID 23572523.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  15. ^ Mace, Peter D.; Riedl, Stefan J. (December 2010). "Molecular cell death platforms and assemblies". Current Opinion in Cell Biology. 22 (6): 828–836. doi:10.1016/j.ceb.2010.08.004. ISSN 1879-0410. PMC 2993832. PMID 20817427.{{cite journal}}: CS1 maint: PMC format (link)
  16. ^ Zhivotovsky, Boris; Samali, Afshin; Gahm, Annie; Orrenius, Sten (1999/07). "Caspases: their intracellular localization and translocation during apoptosis". Cell Death & Differentiation. 6 (7): 644–651. doi:10.1038/sj.cdd.4400536. ISSN 1476-5403. {{cite journal}}: Check date values in: |date= (help)
  17. ^ Druškovič, Mirjam; Šuput, Dušan; Milisav, Irina (2006-12). "Overexpression of Caspase-9 Triggers Its Activation and Apoptosis in Vitro". Croatian medical journal. 47 (6): 832–840. ISSN 0353-9504. PMC 2080483. PMID 17167855. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  18. ^ a b Blasche, Sonja; Mörtl, Mario; Steuber, Holger; Siszler, Gabriella; Nisa, Shahista; Schwarz, Frank; Lavrik, Inna; Gronewold, Thomas M. A.; Maskos, Klaus (2013-03-14). "The E. coli Effector Protein NleF Is a Caspase Inhibitor". PLOS ONE. 8 (3): e58937. doi:10.1371/journal.pone.0058937. ISSN 1932-6203.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  19. ^ Cardone, M. H.; Roy, N.; Stennicke, H. R.; Salvesen, G. S.; Franke, T. F.; Stanbridge, E.; Frisch, S.; Reed, J. C. (1998-11-13). "Regulation of cell death protease caspase-9 by phosphorylation". Science (New York, N.Y.). 282 (5392): 1318–1321. ISSN 0036-8075. PMID 9812896.
  20. ^ a b c d Cardone, Michael H.; Roy, Natalie; Stennicke, Henning R.; Salvesen, Guy S.; Franke, Thomas F.; Stanbridge, Eric; Frisch, Steven; Reed, John C. (1998-11-13). "Regulation of Cell Death Protease Caspase-9 by Phosphorylation". Science. 282 (5392): 1318–1321. doi:10.1126/science.282.5392.1318. ISSN 0036-8075. PMID 9812896.
  21. ^ Rotonda, Jennifer; Nicholson, Donald W.; Fazil, Kimberly M.; Gallant, Michel; Gareau, Yves; Labelle, Marc; Peterson, Erin P.; Rasper, Dita M.; Ruel, Réjean (1996-07-01). "The three-dimensional structure of apopain/CPP32, a key mediator of apoptosis". Nature Structural & Molecular Biology. 3 (7): 619–625. doi:10.1038/nsb0796-619.
  22. ^ Madden, Shane D.; Cotter, Thomas G. (2008-02-01). "Cell Death in Brain Development and Degeneration: Control of Caspase Expression May Be Key!". Molecular Neurobiology. 37 (1): 1. doi:10.1007/s12035-008-8021-4. ISSN 0893-7648.
  23. ^ Hakem, Razqallah; Hakem, Anne; Duncan, Gordon S; Henderson, Jeffrey T; Woo, Minna; Soengas, Maria S; Elia, Andrew; de la Pompa, José Luis; Kagi, David (1998-08-07). "Differential Requirement for Caspase 9 in Apoptotic Pathways In Vivo". Cell. 94 (3): 339–352. doi:10.1016/S0092-8674(00)81477-4.
  24. ^ a b c Druškovič, Mirjam; Šuput, Dušan; Milisav, Irina (2006-12). "Overexpression of Caspase-9 Triggers Its Activation and Apoptosis in Vitro". Croatian medical journal. 47 (6): 832–840. ISSN 0353-9504. PMC 2080483. PMID 17167855. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  25. ^ Engidawork, E.; Gulesserian, T.; Yoo, B. C.; Cairns, N.; Lubec, G. (2001-02-16). "Alteration of caspases and apoptosis-related proteins in brains of patients with Alzheimer's disease". Biochemical and Biophysical Research Communications. 281 (1): 84–93. doi:10.1006/bbrc.2001.4306. ISSN 0006-291X. PMID 11178964.
  26. ^ a b Kelly, Jennifer L.; Novak, Anne J.; Fredericksen, Zachary S.; Liebow, Mark; Ansell, Stephen M.; Dogan, Ahmet; Wang, Alice H.; Witzig, Thomas E.; Call, Timothy G. (2010-11-01). "Germline Variation in Apoptosis Pathway Genes and Risk of Non–Hodgkin's Lymphoma". Cancer Epidemiology and Prevention Biomarkers. 19 (11): 2847–2858. doi:10.1158/1055-9965.EPI-10-0581. ISSN 1055-9965. PMID 20855536.
  27. ^ Park, Jae Yong; Park, Jung Min; Jang, Jin Sung; Choi, Jin Eun; Kim, Kyung Mee; Cha, Sung Ick; Kim, Chang Ho; Kang, Young Mo; Lee, Won Kee (2006-06-15). "Caspase 9 promoter polymorphisms and risk of primary lung cancer". Human Molecular Genetics. 15 (12): 1963–1971. doi:10.1093/hmg/ddl119. ISSN 0964-6906. {{cite journal}}: line feed character in |title= at position 10 (help)
  28. ^ Straathof, Karin C.; Pulè, Martin A.; Yotnda, Patricia; Dotti, Gianpietro; Vanin, Elio F.; Brenner, Malcolm K.; Heslop, Helen E.; Spencer, David M.; Rooney, Cliona M. (2005-06-01). "An inducible caspase 9 safety switch for T-cell therapy". Blood. 105 (11): 4247–4254. doi:10.1182/blood-2004-11-4564. ISSN 0006-4971. PMID 15728125.
  29. ^ a b c d "CASP9 - Caspase-9 precursor - Homo sapiens (Human) - CASP9 gene & protein". www.uniprot.org. Retrieved 2017-11-30.
  30. ^ Vu, Ngoc T.; Park, Margaret A.; Shultz, Jacqueline C.; Goehe, Rachel W.; Hoeferlin, L. Alexis; Shultz, Michael D.; Smith, Sarah A.; Lynch, Kristen W.; Chalfant, Charles E. (2013-03-22). "hnRNP U enhances caspase-9 splicing and is modulated by AKT-dependent phosphorylation of hnRNP L". The Journal of Biological Chemistry. 288 (12): 8575–8584. doi:10.1074/jbc.M112.443333. ISSN 1083-351X. PMC 3605676. PMID 23396972.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
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