CREB Couples Neurotrophin Signals to Survival Messages

A mechanism whereby CREB might regulate cell sur-by neurotrophins that are secreted by their innervation vival during lymphocyte development emerged from targets. If inadequate amounts of neurotrophin are avail-analysis of bcl-2 transcription (Wilson et al., 1996). Bcl-2 able, these dependent neurons undergo programmed belongs to a family of proteins that suppress (e.g., cell death. Since the discovery of NGF decades ago, bcl-2) or induce (e.g., BAD) apoptosis. Certain stimuli many laboratories have sought to understand how neu-that promote B cell survival trigger both CREB phos-rotrophins promote the survival of neurons. These ef-phorylation and bcl-2 transcription. Promoter analysis forts have revealed specific pathways that convert neu-of the 5Ј regulatory region of the bcl-2 gene revealed a rotrophin signals arriving at the plasma membrane into consensus cyclic AMP response element (CRE) that adaptive intracellular biochemical responses. Parallel binds CREB and related family members and whose research into general mechanisms of cell survival has mutation blocks stimulus-induced bcl-2 transcription uncovered highly conserved molecular machinery that (Wilson et al., 1996). Pugazhenthi et al. (1999) extended is responsible for executing programmed cell death. these findings by showing that the growth factor, insulin-How upstream neurotrophin signaling impinges on the like growth factor-1 (IGF-1), induces bcl-2 transcription programmed cell death machinery to promote neuronal in PC12 cells through CREB. CREB regulation of bcl-2 survival has been unclear. Two recent studies have transcription suggested a way that other extracellular shown that neurotrophins inhibit the cell death machin-signals, such as neurotrophins, might promote neuronal ery, partly through the action of the cyclic AMP response survival. element binding protein (CREB) family of transcription In vivo studies suggested that bcl-2 or a close family factors (Bonni et al., 1999; Riccio et al., 1999). This mini-member might mediate neurotrophin-dependent sur-review discusses these findings and relates them to vival. Disruption of bcl-2 led to the postnatal death of known functions of CREB and other transcription-dependent mechanisms of neuronal survival. CREB the Transcription Factor CREB belongs to a family of transcription factors that form homo-and heterodimers through a series of leucine residues and bind to DNA through adjacent basic amino acids (reviewed by Shaywitz and Greenberg, 1999). Diverse extracellular stimuli activate CREB through multiple signaling cascades that converge to phosphorylate a critical residue, Ser-133. The first neurotrophin-induced CREB kinase to be identified was the 90 kDa ribosomal S-6 kinase-2 (RSK-2), a downstream target of the Ras/ ERK pathway (Figure 1). Subsequently, multiple neurotro-phin-induced CREB …