Final Report Summary - CAAXPROCESSINGHUMDIS (CAAX Protein Processing in Human DIsease: From Cancer to Progeria)
The long-term goal of our research is to understand the biochemical importance of the posttranslational processing of CAAX proteins and to define its role in the pathogenesis and treatment of diseases caused by mutant or dysfunctional CAAX proteins (e.g. cancer, inflammation, and progeria). Our recent data challenges the current understanding of the biological role of protein geranylgeranylation—the first CAAX protein processing step. Previous studies had assumed that protein geranylgeranylation, which renders CAAX proteins more hydrophobic, should stimulate membrane binding and activation of the CAAX proteins. We found instead that knockout of the enzyme that carries out protein geranylgeranylation leads to hyperactivation of CAAX proteins, including RAC1 and RHOA, and this leads to inflammatory disorders such as rheumatoid arthritis. This result has challenged the current dogma regarding the role of a major protein posttranslational modification. We also found that reducing the expression of ICMT, a methyltransferase that carries out the last CAAX processing step, eliminated disease phenotypes in mice with progeria, an accelerated aging syndrome. In collaboration with investigators in Singapore, we have developed ICMT inhibitors for testing in mice with progeria and efforts to begin clinical trials in children have been initiated.