Neuronal Survival and Apoptosis
Approximately half of all neurons and >99.9% of the
total number of cells generated during the course of a human lifetime go on to die through a process of apoptosis.
The induction of developmental cell death is a highly regulated process and can be suppressed by a variety of
extracellular stimuli. The ability of trophic factors to promote survival is mediated, at least in part, by the
phosphatidylinositide 3'-OH kinase (PI3K)/c-Akt kinase cascade. Several targets of the PI3K/c-Akt signaling pathway
have been identified that may underlie the ability of this regulatory cascade to promote survival. These substrates
include components of the intrinsic cell death machinery such as the pro-apoptotic Bcl-2 family member BAD as well
as members of the FOXO family of transcription factors.
Growth factor suppression of apoptosis correlates with the phosphorylation and inactivation of multiple proapoptotic proteins, including the Bcl-2 family member BAD. To assess the contribution of BAD inactivation to cell survival, we have generated mice with point mutations in the BAD gene that abolish BAD phosphorylation at specific sites. Using these animals, we have found that BAD phosphorylation protects cells from the deleterious effects of apoptotic stimuli and attenuates death pathway signaling by raising the threshold at which mitochondria release cytochrome c to induce cell death.
The PI3K/c-Akt signaling pathway is also known to control organismal life-span in invertebrates and cell survival and proliferation in mammals by inhibiting the activity of members of the FOXO family of transcription factors, triggering the rapid export of FOXO proteins from the nucleus. We have found that mammalian FOXO proteins are involved in the regulation of a diverse set of cellular responses that include cell cycle regulation, apoptosis, glucose metabolism, and stress response. Transcriptional profiling approaches have been used to identify a number of candidate FOXO target genes that appear to mediate these cellular responses, and we are now in the process of characterizing these targets in detail.
Datta SR, Ranger AM, Lin MZ, Sturgill JF, Ma YC, Cowan CW, Dikkes P, Korsmeyer SJ, Greenberg ME. Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis. Dev Cell. 2002; 3(5):631-643.
Tran H, Brunet A, Grenier JM, Datta SR, Fornace AJ Jr, DiStefano PS, Chiang LW, Greenberg ME. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 2002; 296(5567):530-534.
Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004; 303(5666): 2011-5.
Other research areas:
Activity-Dependent Gene Transcription
Regulation of Translation in Neurons
Neuronal Cell Fate Determination
Synapse Formation and Maintenance
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