<P> The cAMP response element (CRE) is the response element for CREB which contains the highly conserved nucleotide sequence, 5' - TGACGTCA - 3' . CRE sites are typically found upstream of genes, within the promoter or enhancer regions . There are approximately 750,000 palindromic and half - site CREs in the human genome . However, the majority of these sites remain unbound due to cytosine methylation which physically obstructs protein binding . </P> <P> A typical (albeit 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 Ca, which in turn activates a protein kinase . This protein kinase translocates 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 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 image . </P> <P> CREB has many functions in many different organs, and some 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, in rats and in mice (see CREB in Molecular and Cellular Cognition). CREB is necessary for the late stage of long - term potentiation . CREB also has an important role in the development of drug addiction and even more so in psychological dependence . 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 . 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 . </P> <P> Disturbance of CREB function in brain can contribute to the development and progression of Huntington's Disease . </P>

Which of the following does not happen for creb protein to activate a gene