Today's issue of Science brings evidence that CREB (cAMP response element binding protein)-of interest to the Alzheimer's community because of its role in long-term memory and in cell death-is an essential element in the cell survival pathway of nerve growth factor (NGF). The study also identifies the gene bcl-2 as a target of the NGF/CREB pathway.
David Ginty, Antonella Riccio and their colleagues at Johns Hopkins and the University of Pennsylvania demonstrate that CREB is necessary for neuronal survival: cultered sympathetic neurons expressing CREB inhibitors underwent cell death in an NGF-rich medium that otherwise kept the neurons alive. Conversely, the researchers show that CREB is itself sufficient to prevent cell death. In a medium deprived of NGF, neurons survived only if they had been transfected with a gene that produced CREB without the usual NGF stimulus.
Ginty's group also address the question of which NGF-sensitive genes might be dependent on CREB activation. From cDNA clone analyses, they determined that expression of the gene bcl-2 increases dramatically in response to NGF. The gene product, Bcl-2, has been previously shown to be necessary, and sufficient by itself, for sympathetic neurons to survive. The researchers find that CREB is necessary for Bcl-2 transcription to be activated, and that even if CREB is interfered with, cells can be kept alive by experimental overexpression of Bcl-2.
Updates of CREB function are of interest to the Alzheimer's community in light of evidence that impaired growth factor function, affecting CREB in particular, is a feature of aging and of Alzheimer's.—Hakon Heimer
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- Riccio A, Ahn S, Davenport CM, Blendy JA, Ginty DD. Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science. 1999 Dec 17;286(5448):2358-61. PubMed.