Anti-apoptotic function of Rac in hematopoietic cells

Abstract

The small GTP-binding protein Rac plays a pivotal role in the regulation of diverse physiological events including reorganization of the actin cytoskeleton, cell cycle progression, and transformation. Here we show an anti-apoptotic e ect of Rac in interleukin-3-dependent murine hematopoietic BaF3 cells. Activated Rac(G12V), when ectopically expressed in BaF3 cells, rendered the cells resistant to apoptosis upon interleukin-3 deprivation, while activated mutants of Rho and Cdc42 displayed no signi®cant anti-apoptotic e ect. In contrast to activated Ras, which also supports cell survival in the absence of interleukin-3, Rac required fetal bovine serum for the prevention of cell death. The involvement of phosphatidylinositol 3-kinase downstream of Rac was demonstrated by the inhibition of Rac-induced cell survival by wortmannin and LY294002 and the presence of phosphatidylinositol kinase activity in the Rac immunoprecipitate. Furthermore, the serine/threonine kinase Akt was stimulated by activated Rac and fetal bovine serum in a synergistic manner. Rac-induced Akt activation was mediated by phosphorylation of threonine-308 and serine-473. In addition to the phosphatidylinositol 3-kinase/Akt pathway, the p38 mitogen-activated protein kinase pathway was crucial for Rac-dependent survival, whereas p38 mitogen-activated protein kinase was not implicated in Ras-induced anti-apoptotic signaling. These ®ndings provide evidence for the involvement of Rac in survival signaling of hematopoietic cells.

Rac1 and RhoG promote cell survival by the activation of PI3K and Akt, independently of their ability to stimulate JNK and NF-κB

“…In line with our present results, whereas early work indicated that small G proteins of the Rho family do not play a role in Akt regulation (Klippel et al, 1996), more recent studies have shown that Rac1 and 2 can indeed activate Akt in cells of hematopoietic origin, such as Jurkat and BaF3 cells (Genot et al, 2000;Nishida et al, 1999). In T cells, Rac activation of Akt participates in the formation of membrane spikes (Genot et al, 2000), and in BaF3 cells in the viability upon IL-3 removal (Nishida et al, 1999).…”

“…In T cells, Rac activation of Akt participates in the formation of membrane spikes (Genot et al, 2000), and in BaF3 cells in the viability upon IL-3 removal (Nishida et al, 1999). Furthermore, in Rac2-de®cient mast cells, the survival response to growth factors was diminished, and that correlated with a decreased activation of Akt and enhanced BAD/Bcl-X L expression .…”

Rac is activated by erythropoietin or interleukin-3 and is involved in activation of the Erk signaling pathway

“…It has recently been reported that PAK1 is activated by IL-3 and plays a role in anti-apoptotic signaling in IL-3-dependent FL5.12 cells (Schurmann et al, 2000). Furthermore, in IL-3-dependent murine hematopoietic BaF3 cells, a constitutively activated Rac mutant, Rac12V, was shown to render the cells resistant to apoptosis upon IL-3 deprivation (Nishida et al, 1999). These observations implicate Rac in cytokine-receptor signaling and in regulation of growth of hematopoietic cells.…”

Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/IκB Kinase Pathway: Role of Nuclear Factor-κB and Bcl-2

“…Rho GTPases have a role in a number of cellular processes such as cytoskeleton remodeling, transcriptional activation, growth control, metastasis, development, and apoptosis. In particular, several groups have indicated Rac as either positive or negative player in the apoptotic program, depending on the cell line investigated and on the stimulus applied (Nishida et al, 1999;Embade et al, 2000;Deshpande et al, 2000;Pervaiz et al, 2001;Harrington et al, 2002;Murga et al, 2002;Zhang et al, 2004). However, the majority of the reports ascribe a protective role to active Rac1.…”