Characterization and Modulation of Proteins Involved in Sulfur Mustard Vesication
Abstract
Sulfur mustard (SM) causes blisters in the skin through a series of cellular changes that we are beginning to identify. Recently, using chemical inhibitors, we found a major role for Ca(2+) and calmodulin in the induction of differentiation in human keratinocytes in response to SM. We also obtained the unexpected results that SM induces markers of apoptosis, and that this process also proceeds via a Ca(2+)-calmodulin-dependent pathway. We have extended these studies to show that expression of calmodulin antisense RNA blocks the differentiation and apoptotic response of keratinocytes to SM. In addition, using a dominant-negative inhibitor (FADD-DN), we have found that SM-induced apoptosis is also mediated by a FADD-dependent pathway, which induces caspase activation. The involvement of such varied molecules as Ca(2+), calmodulin, and FADD suggests a complex network involved in SM-induced differentiation and apoptosis. However, in our studies to date, we have found that blocking any one of these upstream signals can inhibit terminal differentiation or apoptosis, indicating that these molecular pathways are potential targets for therapeutic intervention. Immortalized keratinocytes stably transfected with FADD-DN form normal epidermis on athymic mice, but have an altered response to SM. We are also currently utilizing retroviral expression vectors expressing calmodulin antisense RNA to modulate the expression of calmodulin, and thus the differentiation and apoptotic pathways in primary keratinocytes and grafted epidermis to alter SM toxicity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2000
- Accession Number
- ADB261754
Entities
People
- Dean S. Rosenthal
Organizations
- Georgetown University