ID: 212: Guanylate-Binding Proteins (GBPs): Large cytokine-induced GTPases that regulate the cytoskeleton

Abstract

Guanylate-Binding Proteins (GBPs) are a family of pro-inflammatory cytokine-induced GTPases. These proteins have been best studied for their anti-microbial activities against pathogens sensitive to IFN- γ . However, GBPs have a number of significant functions not directly related to their antimicrobial activities. One of these is regulation of the cytoskeleton. Integrins, TNF- α , and PDGF all promote rearrangement of the actin cytoskeleton, in part through the activation of the master cytoskeleton regulator Rac. mGBP-2 inhibits these rearrangements by inhibiting their ability to activate Rac. The inhibition of Rac is accompanied by the binding of mGBP-2 to the catalytic subunit of PI3-K and inhibiting its function. mGBP-2 also protects cells from killing by the cytotoxic chemotherapeutic drug, paclitaxel. Paclitaxel is proposed to kill cells by inhibiting the dynamic instability of microtubules. Cells can be protected from paclitaxel by restoration of this dynamic instability. Forced expression of the human ortholog of mGBP-2, hGBP-1, also protects tumor cells from killing by paclitaxel. hGBP-1 mRNA is expressed at greater than 2-fold higher levels than in benign ovaries in only 11–13% of new ovarian tumors. This number was at least 70% for tumors that recurred after a therapeutic regime containing a taxane. While the mechanism(s) by which hGBP-1 protects cells from paclitaxel is still under investigation, one possibility is that this occurs through hGBP-1-mediated alterations in cytoskeletal dynamics.