NF-kappaB couples protein kinase B/Akt signaling to distinct survival pathways and the regulation of lymphocyte homeostasis in vivo.
Protein kinase B (PKBalpha/Akt1) a PI3K-dependent serine-threonine kinase, promotes T cell viability in response to many stimuli and regulates homeostasis and autoimmune disease in vivo. To dissect the mechanisms by which PKB inhibits apoptosis, we have examined the pathways downstream of PKB that promote survival after cytokine withdrawal vs Fas-mediated death. Our studies show that PKB-mediated survival after cytokine withdrawal is independent of protein synthesis and the induction of NF-kappaB. In contrast, PKB requires de novo gene transcription by NF-kappaB to block apoptosis triggered by the Fas death receptor. Using gene-deficient and transgenic mouse models, we establish that NF-kappaB1, and not c-Rel, is the critical signaling molecule downstream of the PI3K-PTEN-PKB signaling axis that regulates lymphocyte homeostasis.
Jones
Russell G
RG
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Saibil
Sam D
SD
Pun
Joyce M
JM
Elford
Alisha R
AR
Bonnard
Madeleine
M
Pellegrini
Marc
M
Arya
Sudha
S
Parsons
Michael E
ME
Krawczyk
Connie M
CM
Gerondakis
Steve
S
Yeh
Wen-Chen
WC
Woodgett
James R
JR
Boothby
Mark R
MR
Ohashi
Pamela S
PS
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D016207:Cytokines; D006706:Homeostasis; D008214:Lymphocytes / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic; D019014:fas Receptor
D016207:Cytokines; D016328:NF-kappa B; D019014:fas Receptor