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Transcript of Caspase
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AKNOWLEDGEMENT
My biggest gratitude to God Almighty the only source of
my strength and wisdom, He made this seminar a hugesuccess. I love you.
I also want to acknowledge my Supervisor Dr. SolomonO. Rotimi, for spending his time and effort, just to
ensure that my seminar end up successfully.
Finally I will like to appreciate my most loving parents
and friend, for all their prayer and support just to keep
me standing throughout this period. I love you all.
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OUTLINE
Introduction to cell death
Types of caspase regulated cell death Caspases definition and types
Role of caspases in cell death
Mechanism of caspase regulation in apoptosis
Mechanism of caspase regulation in
inflammation
Pharmacological importance of caspases in drug
development
Conclusion
References
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SUMMARY
Caspases are family of cysteine aspartatespecific
proteases, which are synthesized as zymogens and are
essential regulators in cell death (Jacobson and Weil,1997). Caspases are categorized into three classes. Two
are main components in apoptosis, which includes
initiator caspases (2, 8, 9, and 10), and executioner
caspases (3, 6, and 7). The third class includesinflammatory caspases (1, 4, 5, and 12) (Alnemri, 1996).
Apoptosis is a type of cell death that is common with all
living organisms, which help them get rid of unwanted
cells during development, normal homeostasis and
disease conditions (Thompson et al ., 1995). Apoptosis
can be stimulated by a number of factors (Ashkenazi
and Dixit, 1998), and caspases are the principal executor
of this process (Thornberry et al., 1998). Other form of
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SUMMARY CONTD
Cell death which may results in inflammation of the cell,
include necrosis and pyroptosis; and all of these
processes are regulated by caspases, which are activated
through proteolysis at specific asparagine residues that
are located within the prodomain subunits. Theimportant function of caspases in these processes makes
them potential targets for drug development (Krammer
et al., 2005). This report therefore entails the role ofcaspases in cell death, as well as the pharmacological
importance of caspases in drug development for the
treatment of different diseases.
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INTRODUCTION
The cell is the smallest but basic structural,
functional and biological unit of any knownliving organisms, that is classified as a living
thing. It is can be said to be dead when:
It has lost the integrity of its plasma membrane.
It has undergone complete dissolution intodiscrete bodies
Its corpse has been engulfed by an adjacent cell.
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CASPASE REGULATED CELL DEATHS
They involve 2 classes:
Programmed cell death (apoptosis). Regulated by 2
groups of caspases:
initiator caspases (2, 8, 9, and 10)
executioner caspases (3, 6, and 7)
Inflammatory cell death (necrosis and pyroptosis).
Regulated by caspase (1, 4, 5, and 12).
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DIAGRAM OF APOPTOTIC AND INFLAMMATORY PATHWAY
Grou 8 ro ect 2009
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MECHANISM OF CASPASE REGULATION IN
APOPTOTIC CELL DEATH.Extrinsic pathway:
Cell death signals at the plasma membrane
FasL binds to the death receptor Fas
Oligomerization of the receptor (Danial and Korsmeyer, 2004).
clustering of the FADD-protein receptors.
FADD bind to the DISC of the menbrane
The role of caspases in cell death is to cleave proteins (Wachmann et al., 2010).
Binding of the initiator caspases (caspase-8 and -10) by FADD and DISC, topromote their activation (Kischkel et al., 1995).
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MECHANISM OF CASPASE REGULATION IN APOPTOTICCELL DEATH CONTD.
Caspase-8 and -10 cleave effector caspases -3.
In some cells, this pathway is enough to induce cell death.
Intrinsic pathway (mitochondria) (Li et al ., 1998).
Release of cytochrome c from the mitochondria into the cytoplasm.
Cytochrome c interacts with Apaf-1, to form the apoptosome complex.
Introduction and activation of caspase-9 (Boatright et al., 2003).
Caspase-9 cleaves to caspase-3
Blebbing, chromatin condensation and DNA fragmentation of the targeted
cell. (Woo, M. et al ., 1998)
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MECHANISM OF CASPASE REGULATION IN INFLAMATORY
CELL DEATH
Pro-inflammatory stimuli induce multi-domain proteins termed NOD-likereceptors, to form multi-protein complexes called inflammasomes.
Inflammasomes promote oligomerization of inflammatory caspases and their
self-activation (Alnemri, T., 2009).
Caspase-1 activation is regulated by inflammasomes.
These inflammasomes recruit the adaptor protein ASC, resulting in the
formation of the ASC focus.
Caspase-1 is processed in the ASC focus and cleaves pro-IL-1B and pro-IL-18
to their mature secreted forms.
CARD-containing inflammasomes, such as NLRC4, bind caspase-1inde endentl of ASC to tri er inflammation. Miao et al., 2011
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CASPASES IN DISEASE THERAPY
INHIBITION
Increased levels of caspase activity are often
observed at sites of cellular damage in a numberof diseases, therefore discovery of drugs that
selectively inhibit inflammatory caspases
(caspase-1, -4, and -5) may help to controlautoimmune diseases like rheumatoid arthritis.
(Hoglen, N.C., et al., 2004).
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CASPASES IN DISEASE THERAPY CONTD
ACTIVATION
Some cancers are characterized by over expression of
IAPs ( examples MILAP) which is found at high levels
in melanomas and are associated with resistance toapoptosis. (Vucic, D., and Stennicke, N., 2000).
Therefore, strategies (such as discovery of drugs) thatcan down regulate IAPs, play an important role, as this
would result in selective activation of caspase-3 and
apoptosis induction in cancer cells. (Schimmer, A.D.,
2004 )
CONCLUSION
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CONCLUSION
In conclusion, caspase family members are at the
most important regulatory networks thatcontrols programmed cell death and
inflammation. Although caspase activity is
necessary for proper development and
homeostasis of organisms, inappropriate
activation or inhibition of caspases in the cell,
can result to dire consequences for human
health.
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REFERENCES
Alnemri, E.S. (1996). Human ICE/CED-3 protease nomenclature in cell. Journal of ClinicalInvestigation 87: 171-172.
Alnemri, T. and Alnemri E. S. (2009). AIM2 activates the inflammasome and cell death in response tocytoplasmic DNA.Molecular Cellular Proteomics 458: 509513.Ashkenazi, A. and Dixit, V.M. (1998). Death receptors: signaling and modulation. Journal of ClinicalInvestigation 281: 13051308.
Boatright, K.M., Renatus, M., Scott, F.L., Sperandio, S., Shin, H., Pedersen, I.M., Ricci, J.E., Edris,W.A., Sutherlin, D.P. and Green, D.R., (2003). A unified model for apical caspase activation. ColdSpring Harbor Perspectives in Biology11: 529541.
Danial, N.N. and Korsmeyer, S.J. (2004). Cell death: critical control points. Cold Spring HarborPerspectives in Biology 116: 205219.
Hoglen, N.C. (2004). Characterization of IDN-6556 (3-{2-(2-tert-butyl-phenylaminooxalyl)-aminopropionylamino}-4-oxo-5-(2, 3, 5, 6- tetrafluoro-phenoxy)-pentanoic acid): a liver-targeted caspaseinhibitor.Journal of Clinical Investigation 309: 634640.
Itoh, N. and Nagata, S. (1993). A novel protein domain required for apoptosis. Mutational analysis of
human Fas antigen. Cold Spring Harbor Perspectives in Biology 268: 1093210937.Jacobson, M.D., Weil, M. and Raff, M.C. (1997). Programmed cell death in animal development.Journal of Clinical Investigation 88: 347 354.
Kischkel, F.C., Hellbard, T.S., Behrmann, I., Germer, M., Pawlita, M., Krammer, P.H. and Peter, M.E.(1995). Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signalingcomplex (DISC) with the receptor. Cold Spring Harbor Perspectives in Biology14: 55795588.
Krammer, P.H. (2000). CD95s deadly mission in the immune system.Journal of Clinical Investigation407: 789795
REFERENCES CONTD
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REFERENCES CONTD.
Li, H., Zhu, H., Xu C.J., Yuan J. (1998). Cleavage of BID by caspase 8 mediates the mitochondrialdamage in the Fas pathway of apoptosis. Cold Spring Harbor Perspectives in Biology94: 491501.
Li, H., Zhu, H., Xu, C.J. and Yuan, J. (1998). Cleavage of BID by caspase 8 mediates the mitochondrialdamage in the Fas pathway of apoptosis. Cold Spring Harbor Perspectives in Biology 94: 491501.
Miao, E.A., Rajan, J.V. and Aderem, A. (2011). Pathway profiling antibodies & reagents. Imgenex 243:206-214.
Schimmer, A.D. (2004). Small-molecule antagonists of apoptosis suppressor XIAP exhibit broadantitumor activity.Journal of Clinical Investigation 5: 2535.
Thompson, C.B. (1995). Apoptosis in the pathogenesis and treatment of disease. Cold Spring HarborPerspectives in Biology 267: 1456 -1462.
Thornberry, N.A. (1997). A combinatorial approach defines specificities of members of the caspasefamily and granzyme B. Functional relationships established for key mediators of apoptosis. Journal ofClinical Investigation 272: 1790717911.
Thornberry, N.A. and Lazebnik, Y. (1998). Caspases: Enemies within. Cold Spring Harbor Perspectivesin Biology 281: 13121316.
Vucic, D. and Stennicke, M. (2000). ML-IAP, a novel inhibitor of apoptosis that is preferentiallyexpressed in human melanomas.Journal of Clinical Investigation 10: 13591366.Wachmann, K., Pop, C., Raam, B.J., Drag, M., Mace, P.D., Snipas, S.J., Zmasek, C., Schwarzenbacher,R., Salvesen, G.S. and Riedl, S.J. (2010). Activation and specificity of human caspase- 10. Cold Spring
Harbor Perspectives in Biology49: 83078315
Woo, M., Hakem, R., Soengas, M.S., Duncan, G.S., Shahinian, A., Kagi, D., Hakem, A., McCurrach,M., Khoo, W., Kaufman, S.A., Senaldi, G., Howard, T., Lowe, S.W. and Mak, T.W. (1998). Essential
contribution of caspase-3/CPP32 to apoptosis and its associated nuclear changes. Cell Death andDifferentiation. 12: 806 - 819
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