CELL STRESS AND APOPTOSIS RESEARCH GROUP

The cellular responses to stress can range from adaptive responses to cell death. One of the classical adaptive responses involves the induction or activation of a family of highly conserved proteins called stress or heat shock protein (Hsps). The major Hsps of mammalian cells include proteins of 110, 90, 70, 60, 40 and 27 kDa. Some Hsp members are constitutively expressed whereas others are expressed only after a period of stress (e.g., rise in temperature, exposure to radiation, viral infection, heavy metals and other toxicants). Induction of these proteins in response to stress confers resistance to subsequent stress (thermotolerance). We have shown that this resistance is due to the inhibition of apoptosis. 

 Apoptosis is a highly regulated form of cell death.  It is fundamental physiological process crucial to maintaining homeostasis in multicellular organisms acting as a counterbalance to cell division.  All animal cells are programmed to undergo apoptosis when they cease to function, are no longer needed or are damaged. Dysregulated apoptosis is the underlying mechanism of a number of human diseases. For example inappropriate apoptosis occurs in certain degenerative diseases, while a reduced level of apoptosis is frequently associated with the development of cancer. 

 Apoptosis is characterized by cell shrinkage, nuclear condensation and oligonucleosomal DNA fragmentation. The biochemical basis for the morphological features of apoptosis, which include nuclear condensation and DNA fragmentation, can be traced to the action of a family of proteases called caspases. Mitochondria play a key role in activating caspases by releasing cytochrome c (cyt- c) into cytosol where it binds to Apaf-1, facilitating pro-caspase-9 processing, followed by caspase-9-mediated activation of pro-caspase-3.

 Since dysregulated apoptosis is the underlying mechanism of a number diseases, therefore, a detailed understanding of the signalling pathway in activation of the apoptotic programme provides us with invaluable information for the development of novel therapeutic strategies for the treatment of apoptosis-mediated diseases. Although a number of signalling pathways involved in apoptosis in higher eukaryotes are already delineated, a number of fundamental biological questions yet remain unanswered. 

 The main fields of interest in our laboratory are:

  1)            Biochemical signalling during apoptosis

The apoptotic programme can be activated in response to many toxic stimuli including cytotoxic drugs and chemicals. The mode of action of these drugs vary considerably, however, most induce apoptosis by causing release of cytochrome c from mitochondria.  The mechanism by which cytochrome c is released from mitochondria is unclear but a number of models are proposed.  We are investigating the mechanism by which cytochrome c is released from the mitochondria. In particular we are interested in role of cross-talk between the endoplasmic reticulum and mitochondria in the process. 

  2)            Characterisation of the molecular components of the cell death machinery in cardiomyocytes

Apoptosis is implicated in cardiomyopathy and in other forms of cardiac disease such as ischaemia/reperfusion injury. However, in adult cardiac myocytes death does not exhibit the classical morphology associated with apoptosis in other cell types, even though DNA fragmentation occurs. Whether these differences in cellular morphology reflect a unique cell death programme or tissue specific differences in caspases or caspase substrates expressed in cardiomyocytes, remains unknown. Since the cytosols of cardiomyocytes contain one of the highest densities of mitochondria of any tissue we are investigating if the molecular components for cytochrome c-mediated caspase activation are expressed and functional in these cells.

  3)        Investigation of the mechanisms involved in inhibition of apoptosis by Hsps

In the last few years we have identified Hsps as regulators of apoptosis. In particular, Hsp27 and Hsp72 have been shown to inhibit the process. Despite an increasing number of reports on the modulation of apoptosis by Hsps very little is known about the mechanism by which the induction of thermotolerance by Hsps can render cells resistant to apoptosis. We are investigating the differential mechanisms by which Hsp27, Hsp72 and Hsp110 exert their anti-apoptotic effects. Our recent data suggests that Hsp27 exerts its effect selectively at the level of the mitochondrion, whilst Hsp72 imparts its effect downstream of mitochondrial cytochrome c release by preventing caspase activation.

 The following projects are currently running in the lab:

• Molecular mechanism of ER stress-induced cell death

• Mechanism of Grp78 mediated cytoprotection in ER stress

• Caspase-12 Biology

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