CREB (cAMP response element-binding) proteins are transcription factors which bind to certain sequences called cAMP response elements (CRE) in DNA and thereby increase or decrease the transcription of certain genes. CREB is highly related (in structure and function) to CREM (cAMP response element modulator) and ATF-1 (activating transcription factor-1) proteins. CREB proteins are active in many animals, including humans. The typical (somewhat simplified) sequence of events is as follows: a signal arrives at the cell surface, activates the corresponding receptor, which leads to the production of a second messenger such as cAMP or Ca2+, which in turn activates a protein kinase. This protein kinase moves to the cell nucleus, where it activates a CREB protein. The activated CREB protein then binds to a CRE region, and is then bound to by a CBP (CREB binding protein) which coactivates it, allowing it to switch certain genes on or off. The DNA binding of CREB is mediated via its basic leucine zipper domain (bZIP domain) as depicted in the picture.
CREB has many functions in many different organs although most of its functions have been studied in relation to the brain. CREB proteins in neurons are thought to be involved in the formation of long-term memories; this has been shown in the marine snail Aplysia, the fruit fly Drosophila melanogaster, and in rats. They are necessary for the late stage of long term potentiation. There are activator and repressor forms of CREB. Flies genetically engineered to overexpress the inactive form of CREB lose their ability to retain long term memory. CREB is also important for the survival of neurons, as shown in genetically engineered mice, where CREB and CREM were deleted in the brain. This study supports the view that disturbance of CREB function in brain can contribute to the development and progression of Huntington's Disease in humans. If CREB is lost in the whole developing mouse embryo, the mice die immediately after birth, again highlighting the critical role of CREB in promoting survival. CREB is also thought to be involved in the growth of some types of cancer.
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