AKNOWLEDGEMENT

My biggest gratitude to God Almighty the only source of my strength and wisdom, He made this seminar a huge success. I love you. I also want to acknowledge my Supervisor Dr. Solomon O. 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.

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

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 includes inflammatory 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

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. The important function of caspases in these processes makes them potential targets for drug development (Krammer et al., 2005). This report therefore entails the role of caspases in cell death, as well as the pharmacological importance of caspases in drug development for the treatment of different diseases.

INTRODUCTION The cell is the smallest but basic structural, functional and biological unit of any known living organisms, that is classified as a living thing. It is can be said to be dead when:
It It

has lost the integrity of its plasma membrane.

has undergone complete dissolution into discrete bodies corpse has been engulfed by an adjacent cell.

Its

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).

DIAGRAM OF APOPTOTIC AND INFLAMMATORY PATHWAY

(Group

project,

2009)

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, to promote their activation (Kischkel et al., 1995).

MECHANISM OF CASPASE REGULATION IN APOPTOTIC CELL 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)

MECHANISM OF CASPASE REGULATION IN INFLAMATORY CELL DEATH

Pro-inflammatory stimuli induce multi-domain proteins termed NOD-like receptors, 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-1 independently of ASC to trigger inflammation. ( Miao et al., 2011)

CASPASES IN DISEASE THERAPY

INHIBITION
Increased

levels of caspase activity are often observed at sites of cellular damage in a number of diseases, therefore discovery of drugs that selectively inhibit inflammatory caspases (caspase-1, -4, and -5) may help to control autoimmune diseases like rheumatoid arthritis. (Hoglen, N.C., et al., 2004).

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 to apoptosis. (Vucic, D., and Stennicke, N., 2000).
Therefore, strategies (such as discovery of drugs) that can 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
In

conclusion, caspase family members are at the most important regulatory networks that controls 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.

REFERENCES
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REFERENCES CONTD
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