B cell growth is controlled by phosphatidylinosotol 3-kinase-dependent induction of Rel/NF-kappaB regulated c-myc transcription.
Rel/NF-kappaB transcription factors regulate the division and survival of B lymphocytes. Here we show that B cells lacking NF-kappaB1 and c-Rel fail to increase in size upon mitogenic stimulation due to a reduction in induced c-myc expression. Mitogen-induced B cell growth, although not markedly impaired by FRAP/mTOR or MEK inhibitors, required phosphatidylinositol 3-kinase (PI3K) activity. Inhibition of PI3K-dependent growth coincided with a block in the nuclear import of NF-kappaB1/c-Rel dimers and a failure to upregulate c-myc. In addition, PI3K was shown to be necessary for a transcription-independent increase in c-Myc protein levels that accompanies mitogenic activation. Collectively, these findings establish a role for Rel/NF-kappaB signaling in the mitogen-induced growth of mammalian cells, which in B lymphocytes requires a PI3K/c-myc-dependent pathway.
Grumont
Raelene J
RJ
The Walter and Eliza Hall Institute of Medical Research, P.O. Box The Royal Melbourne Hospital, 3050, Victoria, Australia.
Strasser
Andreas
A
Gerondakis
Steve
S
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000235:genetics; D016259:Genes, myc / Q000235:genetics*; D020573:Genes, rel; D006706:Homeostasis; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020572:Oncogene Proteins v-rel / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D014158:Transcription, Genetic
D008070:Lipopolysaccharides; D016328:NF-kappa B; D020572:Oncogene Proteins v-rel; D019869:Phosphatidylinositol 3-Kinases