Characterization and Modulation of Proteins Involved in SM Vesication
Abstract
Sulfur mustard (SM) causes blisters in the skin through a series of cellular changes that we are beginning to identify. Previously, we found that SM induces markers of differentiation and apoptosis in human keratinocytes in response to SM. A number of studies in the past several years have shown that the central signaling proteins for many of the pathways that coordinate apoptosis are members of the caspase family of cysteine proteases (named for their preference for aspartate at their substrate cleavage site (Alnemri et al., 1996). Caspases cleave key proteins involved in the structure and integrity of the cell. Previously, we focused on caspase-3 in the SM response. To further understand the apoptotic response, we have devoted much of our effort to assay for the activation of other key caspases. These include the "upstream" caspases 8, 9, and 10, and the "executioner" caspases 3, 6, and 7. We have determined that caspase-8 is the first to be activated after SM treatment. Upregulation of different isoforms of both Fas and Fas ligand are observed following SM exposure. Caspase-6 is the first executioner caspase to be activated, and we have evidence that keratin KI, along with other structural proteins of the cell is cleaved by this caspase. Using retroviral constructs expressing antisense to calmodulin, we also obtained the results that SM-induced apoptosis and differentiation proceeds via a Ca2+-calmodulin-dependent pathway.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2001
- Accession Number
- ADA391085
Entities
People
- Dean S. Rosenthal
Organizations
- Georgetown University