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Cell death in health and disease.

Lockshin RA, Zakeri Z - J. Cell. Mol. Med. (2007)

Bottom Line: Most effort has focused on the machinery of cell death, or the proximate effectors of apoptosis and their closely-associated and interacting proteins.Another complicating factor is that many death-associated proteins may have functions totally unrelated to their role in cell death, generating the possibility of undesirable side effects if one interferes with them.In the future, the challenge will be more to understand the challenge to the cell from a more global standpoint, including many more aspects of metabolism, and work toward alleviating or provoking the challenge in a targeted fashion.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, St. John's University, Queens, NY 11439, USA. lockshin@stjohns.edu

ABSTRACT
Cell death is clearly an important factor in development, homeostasis, pathology, and in aging, but medical efforts based on controlling cell death have not become major aspects of medicine. There are several reasons why hopes have been slow to be fulfilled, and they present indications for new directions in research. Most effort has focused on the machinery of cell death, or the proximate effectors of apoptosis and their closely-associated and interacting proteins. But cells have many options other than apoptosis. These include autophagy, necrosis, atrophy, and stepwise or other alternate means of self-disassembly. The response of a cell to a noxious or otherwise intimidating signal will depend heavily on the history, lineage, and current status of the cell. Many metabolic and other processes adjust the sensitivity of cells to signals, and viruses aggressively attempt to regulate the death of their host cells. Another complicating factor is that many death-associated proteins may have functions totally unrelated to their role in cell death, generating the possibility of undesirable side effects if one interferes with them. In the future, the challenge will be more to understand the challenge to the cell from a more global standpoint, including many more aspects of metabolism, and work toward alleviating or provoking the challenge in a targeted fashion.

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Related in: MedlinePlus

Phenotype resulting from application of the pan-caspase inhibitor, zVAD.fmk, to zebrafish embryos. The notochord (No) is longer than normal and consequently buckles, leading to severe deformity of the embryo.We have not been able to establish that the increased size results from failure of cells to die or directly from the inhibition of caspases. Ey: eye; Yk: yolk. From doctoral research of Nathaniel Abraham.
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fig02: Phenotype resulting from application of the pan-caspase inhibitor, zVAD.fmk, to zebrafish embryos. The notochord (No) is longer than normal and consequently buckles, leading to severe deformity of the embryo.We have not been able to establish that the increased size results from failure of cells to die or directly from the inhibition of caspases. Ey: eye; Yk: yolk. From doctoral research of Nathaniel Abraham.

Mentions: This issue may be defined by asking, what is the ‘day job’ of caspases? Caspases were proteases before they were drafted into service as killers of cells. Some of the caspases, notably interleukin-converting enzyme, function as immune system effectors rather than cell death enzymes. It seems improbable that the entire panoply of caspases, caspase activators and caspase inhibitors floats around the cell only to function at one final instant in the life of the cell. Such a hypothesis is supported by the observation of the pleiotropic effects of caspases.We now know that caspases appear to be involved in differentiation of erythrocytes and lens fibres, proliferation of T lymphocytes, cell migration and sperm differentiation [48–50]. Most of the functions of caspases have been defined in terms of apoptosis, through which they were first recognized, but the enzymes are typically present, though inactive, in viable cells, and activation leads to the demise of the cell. Is it truly reasonable to assume that they play no role in the physiology of the cell other than to wait for a serious threat to the cell? It seems far more likely that one or more initiator or executioner caspases might be activated in very controlled circumstances to fulfil a very different role, or that a pro-caspase might interact with another protein, sequestering it or otherwise affecting the biological activity of the protein; or caspases or interacting molecules might be trafficked from one location to another, limiting the substrates that they could attack. Such an interaction might lead to phenotypes that have no immediate or obvious connection to cell death, as has been reported for several caspase knockouts [51–57]. In another example, inhibition of caspases leads to a pronounced notochordal deformation in zebrafish embryos (Fig. 2).


Cell death in health and disease.

Lockshin RA, Zakeri Z - J. Cell. Mol. Med. (2007)

Phenotype resulting from application of the pan-caspase inhibitor, zVAD.fmk, to zebrafish embryos. The notochord (No) is longer than normal and consequently buckles, leading to severe deformity of the embryo.We have not been able to establish that the increased size results from failure of cells to die or directly from the inhibition of caspases. Ey: eye; Yk: yolk. From doctoral research of Nathaniel Abraham.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401285&req=5

fig02: Phenotype resulting from application of the pan-caspase inhibitor, zVAD.fmk, to zebrafish embryos. The notochord (No) is longer than normal and consequently buckles, leading to severe deformity of the embryo.We have not been able to establish that the increased size results from failure of cells to die or directly from the inhibition of caspases. Ey: eye; Yk: yolk. From doctoral research of Nathaniel Abraham.
Mentions: This issue may be defined by asking, what is the ‘day job’ of caspases? Caspases were proteases before they were drafted into service as killers of cells. Some of the caspases, notably interleukin-converting enzyme, function as immune system effectors rather than cell death enzymes. It seems improbable that the entire panoply of caspases, caspase activators and caspase inhibitors floats around the cell only to function at one final instant in the life of the cell. Such a hypothesis is supported by the observation of the pleiotropic effects of caspases.We now know that caspases appear to be involved in differentiation of erythrocytes and lens fibres, proliferation of T lymphocytes, cell migration and sperm differentiation [48–50]. Most of the functions of caspases have been defined in terms of apoptosis, through which they were first recognized, but the enzymes are typically present, though inactive, in viable cells, and activation leads to the demise of the cell. Is it truly reasonable to assume that they play no role in the physiology of the cell other than to wait for a serious threat to the cell? It seems far more likely that one or more initiator or executioner caspases might be activated in very controlled circumstances to fulfil a very different role, or that a pro-caspase might interact with another protein, sequestering it or otherwise affecting the biological activity of the protein; or caspases or interacting molecules might be trafficked from one location to another, limiting the substrates that they could attack. Such an interaction might lead to phenotypes that have no immediate or obvious connection to cell death, as has been reported for several caspase knockouts [51–57]. In another example, inhibition of caspases leads to a pronounced notochordal deformation in zebrafish embryos (Fig. 2).

Bottom Line: Most effort has focused on the machinery of cell death, or the proximate effectors of apoptosis and their closely-associated and interacting proteins.Another complicating factor is that many death-associated proteins may have functions totally unrelated to their role in cell death, generating the possibility of undesirable side effects if one interferes with them.In the future, the challenge will be more to understand the challenge to the cell from a more global standpoint, including many more aspects of metabolism, and work toward alleviating or provoking the challenge in a targeted fashion.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, St. John's University, Queens, NY 11439, USA. lockshin@stjohns.edu

ABSTRACT
Cell death is clearly an important factor in development, homeostasis, pathology, and in aging, but medical efforts based on controlling cell death have not become major aspects of medicine. There are several reasons why hopes have been slow to be fulfilled, and they present indications for new directions in research. Most effort has focused on the machinery of cell death, or the proximate effectors of apoptosis and their closely-associated and interacting proteins. But cells have many options other than apoptosis. These include autophagy, necrosis, atrophy, and stepwise or other alternate means of self-disassembly. The response of a cell to a noxious or otherwise intimidating signal will depend heavily on the history, lineage, and current status of the cell. Many metabolic and other processes adjust the sensitivity of cells to signals, and viruses aggressively attempt to regulate the death of their host cells. Another complicating factor is that many death-associated proteins may have functions totally unrelated to their role in cell death, generating the possibility of undesirable side effects if one interferes with them. In the future, the challenge will be more to understand the challenge to the cell from a more global standpoint, including many more aspects of metabolism, and work toward alleviating or provoking the challenge in a targeted fashion.

Show MeSH
Related in: MedlinePlus