サイクリックＡＭＰ応答エレメント結合蛋白（ＣＲＥＢ）による細胞増殖およびアポトーシスの制御

Abstract

In this review, we will discuss cyclic AMP response element binding protein (CREB), a cAMP-and Ca2+-dependent transcription factor originally isolated from rat brain, and its roles in diverse cellular activities. In the introduction, we briefly describe the molecular mechanism for transcriptional enhancement by CREB and CREB/ATF family proteins. We also review the biological importance of CREB in long-term memory and T lymphocyte activation established by knockout and transgenic mice, respectively. The involvement of CREB in inflammatory responses through an induction of immunoregulatory and preinflammatoy cytokine genes is also discussed. Then we focus on the possible involvement of CREB in the regulation of cell cycle progression and apoptosis induction, presenting our published data along with our preliminary observations. We show that the expression level of CREB protein highly correlates with the growth activity of the cells and an over-expression of CREB enhances cyclin A expression. Surprisingly, an enforced expression of CREB induces apoptosis. Deletion analysis indicates that neither the transactivation domain nor kinase inducible domain is required but the C-terminal b-Zip structure, consisting of DNA-binding and dimerization domain, and the juxta four amino acids to its N-terminus are important for apoptosis induction, suggesting that the two functions of CREB, transcriptional enhancement and apoptosis induction, are accomplished by distinct mechanisms. The physiological relevance of CREB induced apoptosis and the possible therapeutic applications for diseases with malignant cell proliferation will be discussed.