Sci. Aging Knowl. Environ., 30 January 2002
Trash Talk: AGEs might participate in cell-death signal (Cell death; AGEs)
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/4/nw14
Key Words: AGE advanced glycation end product methylglyoxal necrosis programmed cell death
Abstract: Long deemed sinister, a particular type of molecular junk might serve a crucial cellular purpose. As cells burn sugar to harness the energy contained in its bonds, they create destructive chemicals. Some of these toxicants, such as methylglyoxal (MG), can glom onto proteins, forming advanced glycation end products (AGEs). These troublesome appendages accumulate in aging organisms and perhaps contribute to the tissue deterioration observed in older animals (see "Aging Research Grows Up"). AGEs were originally thought to be junk that gets tangled in protein machines by chance, but new research suggests that they might instead participate in cellular signaling pathways.
Van Herreweghe and colleagues made this discovery by chance while investigating how a protein called tumor necrosis factor (TNF) kills human cancer cells. To understand the molecular changes induced by TNF, they sought proteins that receive a phosphate group in response to TNF exposure. That chemical addition commonly regulates protein activity. TNF treatment of cultured cancer cells caused phosphorylation of a protein called glyoxylase I. Scientists don't fully understand the function of glyoxylase I, but it appears to disarm MG molecules by turning them back into sugar. Knowing that, the team wondered whether phosphorylation of glyoxylase might hinder its ability to eradicate MG; the resulting accumulation of MG might transmit the deadly signal initiated by TNF.
Further experiments support that idea. Cell death by TNF depends on the phosphorylation of glyoxylase I: A chemical that blocks phosphorylation of glyoxylase I--but not other proteins--reduces by 50% the amount of cell death triggered by TNF. In addition, cells treated with TNF contain more MG than do untreated cells. The researchers also found that inhibition of glyoxylase I phosphorylation reduces the amount of AGEs produced by MG. Based in part on these observations, the researchers propose that phosphorylated glyoxylase might help create specific MG-derived AGEs that trigger cell death.
The idea that AGEs carry messages in cell signaling pathways represents a significant shift in thinking, according to biochemist John Baynes of the University of South Carolina, Columbia. Perhaps future work will clarify how phosphorylation tweaks the operation of glyoxylase I and confirm the role of MG in the TNF pathway. But the results hint that AGEs might expunge organismal dirt--cancer cells--rather than just gum up the works.
--R. John Davenport
F. Van Herreweghe, J. Mao, F. W. R. Chaplen, J. Grooten, K. Gevaert, J. Vandekerckhove, K. Vancompernolle, Tumor necrosis factor-induced modulation of glyoxalase I activities through phosphorylation by PKA results in cell death and is accompanied by the formation of a specific methylglyoxal-derived AGE. Proc. Natl. Acad. Sci. U.S.A. 99, 949-954 (2002). [Abstract] [Full Text]
Citation: R. J. Davenport, Trash Talk: AGEs might participate in cell-death signal (Cell death; AGEs). Science's SAGE KE (30 January 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/4/nw14
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