Transcription factor cAMP response element-binding protein CREB

Abstract

The cAMP response element-binding protein (CREB) was identified almost 20 years ago. Since then, CREB has become one of the most extensively studied transcription factors. Currently, the importance of CREB for numerous physiological events has been confirmed by the number of targets: up to 4000 genes or up to 6000 loci. In addition, it is well known that numerous signals, not only the cAMP signal, but also Ca²⁺, cellular stresses and cell cycle systems, regulate CREB activity in a phosphorylation-dependent manner. In mice, knockout models targeting CREB and its cognate factors have disclosed essential functions of the CREB family in cell survival from early embryo to germ cells. By contrast, the CREB family factors are found only in multicellular animals, although cAMP-/stress-dependent gene regulation plays an important role in a variety of organisms, such as Escherichia coli and yeast, indicating that CREB may regulate physiological events acquired by animals during their evolution. In view of these findings, we summarize a new insight of CREB regulation actualized through its basic leucine zipper domain and three physiological events regulated by CREB: ischemia, tumorigenesis and memory. Hiroshi Takemori, Junko Kajimura and Mitsuhiro Okamoto describe transactivation activities encoded by the basic leucine zipper (bZIP) domain. Studies of protein–protein interaction suggest the presence of CREB's transactivation activities outside of its transactivation domain. This notion was confirmed by the discovery of the CREB specific coactivator: transducer of regulated CREB activity (TORC). TORCs are also regulated by phosphorylation, but they are active in their dephospho-forms. The dephosphorylation of TORCs occurs concomitantly with the phosphorylation of CREB. The combination of phosphorylation and dephosphorylation of CREB and TORC allows CREB to regulate CRE-dependent transcription in a variety of spectra. Kazuo Kitagawa reports on the importance of CREB and CRE-mediated gene expression after ischemic stresses. When nerve cells are subjected to sublethal conditions, kinase cascades increase CREB phoshorylation and up-regulate CRE-mediated expression of genes, such as Bcl-2 and brain derived neurotrophic factor, which enhance cell survival. Recent studies also provide evidence that CREB agonists, inhibitors of phosphodiesterase and acetylcholinesterase, protect neurons from stress, thus indicating the neuro-protective function of CREB. Hao Wu, Yang Zhou and Zhi-Qi Xiong deal with a mechanism by which CREB maintains memory and learning in the brain. Neuronal actions/signals are classified into two categories, nongenomic actions and genomic actions. The latter occurs in the late phase of signal transduction, and memory is established through long-term synaptic potentiation. However, CREB phosphorylation is mediated by nongenomic actions that occur in the acute phase and diminish in the late phase. TORC1 is abundantly expressed in the hippocampus and plays an important role in the prolonged activation of CREB under the regulation of cAMP/Ca²⁺ signaling. Yeung-Tung Siu and Dong-Yan Jin describe the involvement of CREB in oncogenesis. Escape from cell death is an essential mechanism for cells to become immortalized. Excessive and prolonged activation of CREB then maintains cell proliferation. Some of the gene-realignments that produce chimeric proteins of oncogenic factors with CREB and its related factors induce constitutive activation of CRE-dependent transcription followed by onsets of tumorigensis. Viruses also utilize CREB for their transcription and replication, and some viral proteins consistently keep CREB activated, which then becomes a factor in virus-mediated tumorigensis. The identification and clarification of the physiological roles of CREB and its regulatory mechanisms disclosed by these studies can be expected to lead to an acceleration in related discoveries in the not too distant future.