PreprintCited by 4,216Cell death mechanisms and regulationPI3K/AKT/mTOR signaling in cancerNerve injury and regeneration

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Cellular survival: a play in three Akts

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Datta, S. R., Brunet, A., Greenberg, M. E.·1999·Genes & Development

DOI 10.1101/gad.13.22.2905

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Abstract

The programmed cell death that occurs as part of normal mammalian development was first observed nearly a century ago (Collin 1906). It has since been established that approximately half of all neurons in the neuroaxis 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 (for review, see Datta and Greenberg 1998; Vaux and Korsmeyer 1999). The induction of developmental cell death is a highly regulated process and can be suppressed by a variety of extracellular stimuli. The purification in the 1950s of the nerve growth factor (NGF), which promotes the survival of sympathetic neurons, set the stage for the discovery that peptide trophic factors promote the survival of a wide variety of cell types in vitro and in vivo (Levi-Montalcini 1987). The profound biological consequences of growth factor (GF) suppression of apoptosis are exemplified by the critical role of target-derived neurotrophins in the survival of neurons and the maintenance of functional neuronal circuits. (Pettmann and Henderson 1998). Recently, the ability of trophic factors to promote survival have been attributed, at least in part, to the phosphatidylinositide 38-OH kinase (PI3K)/c-Akt kinase cascade. Several targets of the PI3K/c-Akt signaling pathway have been recently identified that may underlie the ability of this regulatory cascade to promote survival. These substrates include two components of the intrinsic cell death machinery, BAD and caspase 9, transcription factors of the forkhead family, and a kinase, IKK, that regulates the NF-kB transcription factor. This article reviews the mechanisms by which survival factors regulate the PI3K/c-Akt cascade, the evidence that activation of the PI3K/c-Akt pathway promotes cell survival, and the current spectrum of c-Akt targets and their roles in mediating c-Akt-dependent cell survival.

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Authors: Datta, S. R., Brunet, A., & Greenberg, M. E.
Affiliations: Boston Children's Hospital (US)
ORCID: Datta, S. R.
Brunet, A.
Greenberg, M. E.
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 1999-11-15
Volume: 13
Issue: 22
Pages: 2905-2927
ISSN: 0890-9369 (ISSN-L)
DOI: 10.1101/gad.13.22.2905
OpenAlex: W2147114673
Cited by: 4,216
References: 233
Citations by year: 2026: 27 · 2025: 36 · 2024: 45 · 2023: 47 · 2022: 60 · 2021: 68 · 2020: 87 · 2019: 86 · 2018: 81 · 2017: 94 · 2016: 90 · 2015: 140 · 2014: 136 · 2013: 149 · 2012: 150
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
PubMed (publishedVersion)
Funders: Bentham-Moxon Trust
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
Keywords: cell survival, apoptosis, PI3K/Akt signaling, neurotrophins, trophic factors, developmental cell death, Bad, caspase-9, forkhead transcription factor, IκB kinase, NF-kB, neuronal survival, growth factor signaling
MeSH terms: Animals, Carrier Proteins, Cell Survival, Cell Transformation, Neoplastic, Humans, Phosphatidylinositols, Phosphorylation, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Substrate Specificity, Transcription Factors, Signal Transduction, NF-kappa B, Sequence Alignment, Apoptosis, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Phosphatidylinositol 3-Kinases, Protein Isoforms, Caspases, Glycogen Synthase Kinase 3, bcl-Associated Death Protein, Proto-Oncogene Proteins c-akt, Mice, Rats, I-kappa B Kinase, Caspase 9

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Cellular survival: a play in three Akts

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