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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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