CRE protein

Conditional lineage-restricted ablations can be obtained through the incorporation of an inducible system into a transgenic regime. Here the Cre protein can be induced where and when appropriate. This can either be achieved by placing the Cre gene under the control of an inducible promoter (either ubiquitous or lineage-specific) or to construct the Cre cassette as an inducible fusion protein. 

Biosynthesis. CRE is derived from a precursor of 196 amino acids (84,85). This gene contains one copy of CRE, which is flanked by double basic amino acids. The amino acid sequence of the CRE precursor suggests that it may arise from proteins related to POMC and neurophysins (31). The CRE precursor contains a cAMP responsive element which aHows stimulation of mRNA synthesis when intraceHular levels of cAMP are increased (86). 

Pig. 3. Representation of promoter sites on the pro-enkephalin gene. The numbers represent the distance in nucleotides from the pro-enkephalin initiation codon the arrow indicates the direction of transcription. The TATA promoter box occurs immediately before the pro-enkephalin initiation site the AP-2 site, which binds immediate-early gene products, is 70 nucleotides upstream, and the CRE site, which binds a regulatory protein involved in cAMP induction of mRNA synthesis, is 107 nucleotides upstream from the initiation codon. The expanded section shows that the CRE site actually consists of two elements, ENKCRE-1 and ENKCRE-2, which separately confer cAMP sensitivity to pro-enkephalin mRNA synthesis. 

CREB stands for cyclic-AMP response element (CRE) binding protein and is a transcription factor. When phosphorylated by cyclic AMP- and cyclic GMP-dependent Protein Kinases or other protein kinases it binds to gene promoters that contain a specific binding site. After binding, the respective transcription activity is modulated. 

The cAMP responsive element binding factor (CREB) is also activated by phosphorylation. Depending on the stimuli, CREB is the target of a cAMP dependent protein kinase or of kinases called MAPKs, RSK, and CamKIV. As in AP-1, CREB carries a basic leucine zipper motif (bZDP), which mediates homo dimerization of CREB when bound to the CRE. 

The H2 receptor is the second class of HA receptors. This is another G-protein-coupled receptor but, unlike the Hi receptor, the H2 receptor is coupled to adenylyl cyclase via the GTP-binding Gs protein (Hill et ah, 1997). Encoded by an intronless gene and located on human chromosome 5, the H2 receptor is made up of c. 358 amino acids (Gantz et ah, 1991 Traiffort et ah, 1995). Activation of the H2 receptor causes an accumulation of cAMP and activation of protein kinase A that eventually leads to the activation of cyclic-AMP-response element (CRE)-binding protein (CREB) (Hill et ah, 1997). In neurons, the H2 receptor mediates its excitatory effects by blocking the Ca2+-dependent K+ channel (Haas Konnerth, 1983). 

P = constitutive promoter, tetR = TETrepressor gene,TETR = TET repressor protein, tetO = TET operator sequence, = tetracycline, ere/CRE = Cre recombinase gene/protein, PLEA = late embryogenesis abundant promoter, RIP = gene for ribosome inactivating protein, shaded blocks are loxP sites in orientation shown by solid triangle. After [48]... 

The details of the mechanism by which CREB influences gene expression are becoming increasingly understood (Fig. 23-9) [62, 63]. In the basal, or unstimulated, state, CREB is bound to its CREs but does not alter transcriptional rates under most circumstances. Stimulation of a cell by a variety of first messengers leads to the phosphorylation and activation of CREB, which then leads to the regulation of gene transcription. Such phosphorylation of CREB occurs on a single serine residue, serine 133, and can be mediated by one of several protein kinases. 

CREB CRE-binding protein GABA-T GABA transaminase... 

CREM CRE-modulatory protein GAD glutamic acid decarboxylase... 

Newell CL, Deisseroth AB, Lopezberestein G. Interaction of nuclear proteins with an Ap-1 Cre-like promoter sequence in the human TNF-a gene. J Leukocyte Biol 1994 56 27-35. 

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