Department of Medicine , Hennepin County Medical Center , Minneapolis , Minnesota , USA .
Kidney Int Suppl 52 : S29-33 ( 1995)
Abstract
Protein prenylation , the post-translational attachment of isoprenoids to certain cellular proteins , increases protein hydrophobicity and promotes protein-membrane interactions .
Of the many cellular proteins that undergo protein prenylation , particular attention has been paid to the protooncogene product Ras .
Prenylated Ras protein localizes to the inner cell membrane and appears to function as a "molecular switch" ; through which peptide growth factors such as PDGF , IGF-1 , and FGF , and cytokines such as IL-2 , IL-6 , and GM-CSF stimulate intracellular events .
Binding of these substances to their respective receptors on target cells can activate Ras , triggering intracellular signaling cascades which culminate in processes such as cell proliferation , differentiation , and T-cell activation .
Protein prenylation inhibitors block Ras prenylation , prevent membrane localization of Ras , and inhibit growth and proliferation of a variety of cell types .
Recent studies in our laboratory have begun to examine the possible role of Ras in chronic allograft rejection .
Abdominal aorta segments from donor Lewis rats were transplanted into Buffalo recipient rats .
Recipients treated with the HMG-CoA reductase inhibitor lovastatin , which inhibits isoprenoid production , showed significantly decreased allograft intimal area after weeks , when compared with untreated recipients .
In a separate study , recipients treated with the agent leflunomide , which inhibits growth factor receptor tyrosine kinases that can activate Ras , had significantly decreased allograft intimal area after 12 weeks .
These results suggest that Ras may be important in chronic allograft rejection , and that agents that interfere with Ras protein prenylation or activation by growth factor receptors may ameliorate chronic rejection .