Is CREB a key to neuronal survival?

doi:10.1016/S0166-2236(99)01500-3

Trends in Neurosciences

Volume 23, Issue 2, 1 February 2000, Pages 48-53

https://doi.org/10.1016/S0166-2236(99)01500-3 Get rights and content

Abstract

A range of molecules control nerve-cell survival in the brain. Many of these molecules might be neuroprotective through activation of the transcription factor cAMP-response-element-binding protein (CREB). Activation of CREB, by phosphorylation of Ser133, occurs in brain-damage-resistant hippocampal dentate granule cells and is triggered by neuroprotective environmental stimulation. In addition, the Akt neuroprotective signaling pathway activates CREB, and CREB synthesis and phosphorylation promote the survival of many cells, including neurons, in vitro. Thus, CREB might be responsible for programmed nerve-cell survival. Studies investigating its role in the brain are now required to confirm these in vitro results, and the downstream survival genes, whose expression is activated by CREB in neurons, need to be identified.

Section snippets

CREB transcriptional regulation

CREB is a member of a large family of structurally related transcription factors, including activating transcription factor 1 (ATF1), ATF2 (also know as CREBP1), ATF3 and ATF4, which bind to cAMP-response-element (CRE) promoter sites on target genes. The CREB protein can exist in three alternatively spliced isoforms, α, β and Δ, which have different properties and developmental regulation. CREB has been implicated in the transcriptional control of numerous genes, many of which are rapidly

Selective vulnerability in the hippocampus

In its active form, CREB has been shown to regulate many aspects of neuronal functioning, including neuronal excitation¹², development¹³ and long-term synaptic plasticity¹⁴. Recent evidence suggests that CREB might also be involved in an active process of neuroprotection, which therefore explains the selective vulnerability of the hippocampus to brain injury. The hippocampal subregions show a distinct pattern of cell death in response to a number of insults, in particular after prolonged

CREB activation and cell survival

The persistent phosphorylation of CREB in response to stressful stimuli is not restricted to the in vivo situation, and has been demonstrated in PC12 cells following hypoxia⁴ and okadaic-acid treatment²³. Although, in both cases, increased levels of pCREB are likely to underlie numerous adaptive changes, many of which will be unrelated to cell viability, the delayed timecourse is consistent with the idea that at least part of this induction is involved in a cell-survival mechanism. In support

Survival factors and CREB phosphorylation

While there is growing evidence to support the link between the activation of CREB and programmed cell survival, the identity of the upstream initiators of this signaling pathway in the resistant neurons remains unclear. The endogenous neuroprotective agent, brain derived neurotrophic factor (BDNF) is a potential candidate in this respect, as it is co-localized with phosphorylated CREB in the dentate granule cells following hypoxic ischemia¹⁷ (Fig. 2). This observation supports the idea that

CREB-induced gene expression

The identities of target genes regulated by CREB in the resistant dentate granule cells after brain injury remain elusive, even though there are likely to be numerous candidates, many of which have not yet been identified. The Bcl2 gene might be one example, as the phosphorylation of CREB proteins has been shown to have a major role in the induction of its expression during activation of mature B cells and during the rescue of immature B cells from Ca²⁺-dependent apoptosis⁵⁵. The Bcl2 gene

Concluding remarks

There is a rapidly growing body of evidence to support the concept that endogenous CREB activation might provide a potent survival signal in times of cellular stress. Not only has CREB phosphorylation been implicated in the resistance of cells to various insults, but a number of well-established neuroprotective agents exert their actions via pathways that converge on the CREB protein. In particular, there is now evidence that the Akt signaling pathway could lead to CREB phosphorylation and that

Acknowledgements

The authors acknowledge financial support from the Health Research Council of New Zealand and the gift of BDNF antibody from Q. Yan (Amgen). The authors also thank their collaboratos Matthew During, Alexander Muravlev, Ray Xu, Ernest Sirimanne and Peter Gluckman.

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Trends in Neurosciences

ViewpointIs CREB a key to neuronal survival?

Abstract

Section snippets

CREB transcriptional regulation

Selective vulnerability in the hippocampus

CREB activation and cell survival

Survival factors and CREB phosphorylation

CREB-induced gene expression

Concluding remarks

Acknowledgements

Trends Neurosci.

Neurosci. Biobehav. Rev.

Cell

J. Biol. Chem.

J. Biol. Chem.

Brain Res.

Brain Res. Rev.

Mol. Brain Res.

Brain Res. Rev.

Mol. Brain Res.

Mol. Brain Res.

Neuroscience

Brain Res.

Mol. Brain Res.

Mol. Brain Res.

J. Biol. Chem.

Immunobiology

Brain Res.

Mol. Cell. Neurosci.

Neuron

Neuron

Neuron

Regul. Pept.

Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

Hypoxia induces phosphorylation of the cyclic AMP response element-binding protein by a novel signaling mechanism

J. Biol. Chem.

Protein kinase A dependent activator in transcription factor CREB reveals new roles for CREM repressors

Nature

Characterization of motifs which are critical for activity of the cyclic AMP responsive transcription factor CREB

Mol. Cell. Biol.

Viewpoint
Is CREB a key to neuronal survival?