What is apoptosis? Apoptosis is a form of cell death that is controlled by our body. In the case of cancer, what are the mechanisms that suppress this process but promote cell death in neurodegeneration¹? How do the different forms of caspases² activates apoptosis and inflammation? A group of researchers are investigating on the functions and specificities of death and inflammatory caspases as well as the targets of the transcription factor c-Jun³ in mammalian cell death and differentiation.
When susceptible cells receive a death signal, caspases are proteolytically activated, leading to selective protein degradation that promotes apoptosis. The group discovered that in MCF-7 breast carcinoma cells, caspase-3 gene is functionally deleted and that this gene is essential for the typical morphological changes of apoptosis induced by cancer drugs or tumour necrosis factor⁴ (TNF). In their findings, it is indicated that the suppression of caspases may contribute to tumorigenesis⁵. They also showed that a tumour suppressor protein, retinoblastoma, is an important caspase substrate in drug and TNF induced apoptosis of cancer cells. They are currently performing microarrays and targeted knock out of caspase and other apoptosis-related genes in human tumour cell lines in order to study their functions in detail, particularly in apoptotic stress responses.
In our body immune system, when there is a bacterial infection, inflammatory caspases, interleukins⁶ and an anti-apoptotic state in macrophage are activated by bacterial products and one such example is lipopolysaccharide (LPS). The researchers characterized the caspase-1 family that is needed for producing interleukins in macrophages. The caspase-5 family is shown to be up regulated by LPS and may play a part in the inflammatory response to LPS. The group discovered that the function of cathepsin B, a type of lysosomal protease is critical in mediating caspase-1 dependent interleukin-18 maturation that is triggered by nigericin, a microbial toxin. Dr. Porter, one member of the group said that little is known of the caspase-dependent pathways stimulated by bacterial infections that lead to the synthesis of inflammatory interleukins in immune responses and septicaemia⁷.
Strokes, physical injury and neurodegenerative disorders like Parkinson’s disease, cell death in the brain is disrupted by excessive nitric oxide. The group has shown that a neural cell adhesion molecule, NCAM140, an isoform of the molecule, is regulated by c-Jun⁸, mediating both neuronal differentiation of neuroblastoma cells and their protection from NO-induced apoptosis. They discovered that c-Jun modification via phosphorylation at its N-terminus promotes NO-induced apoptosis. These findings help to explain how c-Jun can dictate whether a cell lives or dies. The group is poised to identify additional transcription factors and the genes that they regulate which determine cellular sensitivity to NO-induced apoptosis. The results should help us to better understand the mechanisms underlying the deleterious actions of excessive NO in the brain.
1- Progressive loss of structure or function of neurons, including death of neurons
2- A family of cysteine proteases, which play essential roles in apoptosis (programmed cell death), necrosis and inflammation.
3- A gene and protein which, in combination with c-Fos, forms the AP-1 early response transcription factor.
4- A group of cytokines family that can cause cell death.
5- A process whereby normal cells are transformed into tumour cells.
6- A group of cytokines like macrophages.
7- Presence of pathogenic organisms in the blood stream.
8- A gene and protein
Reference: http://www.a-star.edu.sg/biomedical_sciences/304-Project?iid=1
Additional Information:
R.U. Janicke, P.A.Walker, X.Y. Lin and A.G. Porter
Specific cleavage of the retinoblastoma protein by an ICE-like protease in apoptosis.
EMBO J. 15: 6969-78, 1996.
R.U. Janicke, M.L. Sprengart, M.R. Wati and A.G. Porter
Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis.
J. Biol. Chem. (Communication) 273: 9357-60, 1998.
X.Y. Lin, M.S.K. Choi and A.G. Porter.
Expression analysis of the human caspase-1 subfamily reveals specific regulation of the CASP5 gene by lipopolysaccharide and interferon-?.
J. Biol. Chem. 275: 39920-6, 2000.
Z. Feng, L. Li, P. Y. Ng and A. G. Porter
Neuronal differentiation and protection from nitric oxide-induced apoptosis requires c-Jun-dependent expression of NCAM140.
Mol. Cell. Biol. 22: 5357-66, 2002.
H. Hentze, X.Y. Lin, M.S.K. Choi and A.G. Porter
Critical role for cathepsin B in mediating caspase-1-dependent IL-18 maturation and caspase-1-independent necrosis triggered by the microbial toxin nigericin.
Cell Death Differ. In press, 2003
Ernest Koh 41906972
