Hypothesis: Thalidomide embryopathy - Proposed mechanism of action

We propose that thalidomide affects the following pathway during limb devel opment: Growth factors (FGF-2 and IGF-1) attach to receptors on limb bud me senchymal cells and initiate some second messenger system (perhaps SP-1), w hich activates alpha v and beta 3 integrin subunit genes. The resulting alp ha v beta 3 integrin proteins stimulate angiogenesis in the developing limb bud. Several steps in this pathway depend on the activation of genes with primarily GC promoters (GGGCGG). Thalidomide, or a hydrolysis or metabolic breakdown product, specifically binds to GC promoter sites and inhibits the transcription of those genes. inhibition of the genes interferes with norm al angiogenesis, which results in truncation of the limb. (C) 2000 Wiley-Li ss, Inc.