The small GTPase Rac suppresses apoptosis caused by serum deprivation in fibroblasts.
BACKGROUND
The small GTPase Rac1 is a key signaling protein that mediates a number of important physiologic functions including the organization of the actin cytoskeleton, lipid metabolism, and gene transcription. Rac1 has also been implicated in oncogenic transformation. Expression of constitutively active Rac1 in Rat1 fibroblasts elicits serum- and anchorage-independent growth and causes tumorigenicity in nude mice. The signaling pathways that mediate the role of Rac in cell transformation remain to be identified. Here, we study the role of Rac in cell survival in the absence of serum.


METHODS
The cell lines used in this study are Ratl fibroblasts that express constitutively active or dominant negative mutants of Rac1. We used long-term video time-lapse microscopy to analyze the effects of these Rac1 mutants on mitogenicity and apoptosis.


RESULTS
We show that the increase in viability, which is stimulated by Rac1 in the absence of serum, is predominantly caused by an inhibition of apoptosis, with a minor increase in cell division. We also show that Rac1-stimulated cell viability in serum-starved cells is inhibited by chemical inhibition of phosphatidylinositol 3-kinase.


CONCLUSIONS
Our observations indicate a role for Rac1 in survival signaling, possibly via activation of phosphatidylinositol 3-kinase. We propose that Rac1-stimulated cell survival may contribute to the role of Rac1 in serum-independent growth and cell transformation.
Ruggieri
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R
Onyx Pharmaceuticals, Richmond, CA, USA. mruggieri@picower.edu
Chuang
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YY
Symons
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M
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology*; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors*; D017930:Genes, Reporter; D007106:Immune Sera; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D018715:Microscopy, Video; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000502:physiology*
D016895:Culture Media, Serum-Free; D020690:GTPase-Activating Proteins; D007106:Immune Sera; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020830:rac1 GTP-Binding Protein