Level of HgCl2-mediated phosphorylation of intracellular proteins determines death of thymic T-lymphocytes with or without DNA fragmentation
✍ Scribed by Anwarul A. Akhand; Masashi Kato; Haruhiko Suzuki; Toshio Miyata; Izumi Nakashima
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 205 KB
- Volume
- 71
- Category
- Article
- ISSN
- 0730-2312
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✦ Synopsis
Exposure to Hg 2ϩ at a wide range of concentrations (approximately 1-100 µM) more or less caused the death of murine thymic T-lymphocytes, and exposure to 1 µM but not 10 µM (or more) of Hg 2ϩ induced DNA fragmentation. Exposure of cells to Hg 2ϩ caused phosphorylation of multiple cellular proteins at the tyrosine residue in a concentration-dependent manner. We found that not only the DNA fragmentation induced by 1 µM Hg 2ϩ but also the cell death bypassing DNA fragmentation caused by 10 µM or more Hg 2ϩ was partly inhibited by protein kinase inhibitors such as staurosporine and herbimycin A. This result suggested the involvement of a protein phosphorylation-linked signal in the mechanism of the Hg 2ϩ -mediated cell death with or without DNA fragmentation. Analysis of proteins by both one-and two-dimensional electrophoresis and immunoblot showed that a 52-kDa Shc protein was heavily phosphorylated by an early signal delivered by a high concentration of Hg 2ϩ , which also phosphorylated extracellular signal-regulated kinase 1 (ERK1; p44) and ERK2 (p42) of the mitogen-activated protein kinase (MAPK) family in a concentration-and time-dependent manner. The c-Jun amino terminal kinase (p54), which is a distant relative of the MAPK family, was also phosphorylated by the treatment with Hg 2ϩ . This eventually formed the signaling cascade that ended with a nuclear target by phosphorylating c-jun at the serine 73. This phosphorylation of c-jun was inhibited by staurosporine. These results suggest that a high level of Hg 2ϩ -mediated protein phosphorylation-linked signal induces rapid cell death bypassing DNA fragmentation, whereas a lower level induces cell death accompanying DNA fragmentation. This conclusion in turn implies that DNA fragmentation is not always a prerequisite for the signal transduction-dependent cell death of T-lymphocytes.