Transcription factors CREB protein

Kurokawa R, Kalafus D, OgUastro MH, Kioussi C, Xu L, Torchia J, Rosenfeld MG, Glass CK (1998) Differential use of CREB binding protein-coactivator complexes. Science 279 700-703 Kwok RP, Lundblad JR, Chrivia,JC, Richards JP, Bachinger HP, Brennan RG, Roberts SG, Green MR, Goodman RH (1994) Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature 370 223-226... 

One mechanism by which CBP and p300 could contribute to neuronal survival is through the transcription factor CREB (cAMP response element binding protein). Normally, activated CBP binds to CREB and acetylates the latter at three putative acetylation sites within its activation domain (Lu et al, 2003). It has been proposed... 

Specific transcription factors bind to enhancer regions or, in a few cases, to silencers and mod-ciate the formation of the initiation complex, thus regulating the rate of initiation of transcription. Each gene contains a variety of enhancer or silencer sequences in its regulatory region. The exact combination of specific transcription factors available (and active) in a particular cell at a particular time determines which genes will be transcribed at what rates, because specific transcription factors are proteins, their expression can be cell-type specific.. Additionally, hormones may regulate the activity of some specific transcription factors. Examples include steroid receptors and the CREB protein. 

An example of specific transcriptional control is cyclic AMP-dependent regulation of genes that have a cyclic AMP response element (CRE) through the action of the transcription factor CREB (cyclic AMP response element binding protein. Figure 12-5). 

Of the protein kinases, protein kinase A is the best investigated and characterized (review Francis and Corbin, 1994). The functions of protein kinase A are diverse. Protein kinase A is involved in the regulation of metabolism of glycogen, lipids and sugars. Substrates of protein kinase A may be other protein kinases, as well as enzymes of intermediary metabolism. Protein kinase A is also involved in cAMP-stimulated transcription of genes that have a cAMP-responsive element in their control region (review Montminy, 1997). An increase in cAMP concentration leads to activation of protein kinase A which phosphorylates the transcription factor CREB at Ser 133. CREB only binds to the transcriptional coactivator CBP in the phosphorylated state and stimulates transcription (see Chapter 1.4.4.2). 

Coupled folding and binding is a frequent theme in the field of intrinsically disordered proteins (see Chap. 6). One of the earliest examples of this phenomenon was the interaction of the phosphorylated kinase-inducible domain (pKID) of the transcription factor CREB with the KIX domain of the transcriptional coactivator CBP. Free pKID is unfolded in solution [21], but folds into an orthogonal pair of helices, aA and aB, upon binding to the folded KIX domain (Fig. 1.5) [23]. We have recently posed the question, what is the... 

Figure 16.2. Signaling for memory formation. Short-term memory formation involves the activation of PKA, but no gene transcription. Activation of G-protein coupled receptors by excitatory stimuli activates adenylyl cyclase. This leads to the elevation of cAMP level, which subsequently activates PKA. Activated PKA undertakes modulation of channels thereby enhancing conductivity. However, prolonged/ repeated activation of this system results in nuclear translocation of PKA, which is the central molecular basis of long-term memory formation. Activated PKA and MAPK activate transcription factor CREB-1 while suppressing the inhibitory CREB-2. Activated CREB-1 binds to CRE region in promoters of early genes like C/EBP. Interestingly, C/EBP itself is a transcription factor that subsequently teams up with CREB to express late memory genes.

Kwok RP, Lundblad JR, Chrivia JC, Richards JP, Bachinger HP, et al. 1994. Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature... 

Protein kinase A serves to phosphorylate a set of tissue-specific substrate enzymes or transcription factors (CREB), thereby affecting their activity. 

In view of the participation of protein kinases and phosphatases in ABA signalling it is likely that constitutively bound transcription factors on ABA inducible genes could be regulated by phosphorylation or dephosphorylation. Activation of transcription by the mammalian bZIP transcription factor CREB is induced by phosphorylation of a serine... 

Histone acetylase activity has been associated with a number of transcription factors and co-activators. The proteins ACTR (activator of the thyroid and retinoic acid receptor) and SRC-1 (steroid receptor co-activator) are involved in activation of transcription by several ligand-bound nuclear receptors, and both contain histone acetylase activity. TAF250, a component of TFIID, also contains histone acetylase activity, as does the co-activator p300/CBP (CREB binding protein), which interacts with the transcription factor CREB. 

Nonreceptor kinases, such as protein kinase A, also regulate transcription factors through phosphorylation. Many hormones generate the second messenger cAMP, which activates protein kinase A. Activated protein kinase A enters the nucleus and phosphorylates the transcription factor CREB (cAMP response element binding protein). CREB is constitutively bound to the DNA response element CRE (cAMP response element) and is activated by phosphorylation. Other hormone signaling pathways, such as the MAP kinase pathway, also phosphorylate CREB (as well as many other transcription factors). 

Phosphoenolpyruvate carboxykinase is induced. Oxaloacetate produces PEP in a reaction catalyzed by PEPCK. Cytosolic PEPCK is an inducible enzyme, which means that the quantity of the enzyme in the cell increases because of increased transcription of its gene and increased translation of its mRNA. The major inducer is cyclic adenosine monophosphate (cAMP), which is increased by hormones that activate adenylate cyclase. Adenylate cyclase produces cAMP from ATP. Glucagon is the hormone that causes cAMP to rise during fasting, whereas epinephrine acts during exercise or stress. cAMP activates protein kinase A, which phosphorylates a set of specific transcription factors (CREB) that stimulate transcription of the PEPCK gene (see Chapter 16 and Pig. 16.18). Increased synthesis of mRNA for PEPCK results in increased synthesis of the enzyme. Cortisol, the major human glucocorticoid, also induces PEPCK. 

One such hypotheses submits that most antidepressants enhance the expression of cyclo-AMP response element binding protein (CREB), which is a transcription factor that after phosphorylation binds to cyclo-AMP response elements localized in the promoter region of many genes including that coding for brain... 

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. 

A sequence stretch 300 base pairs upstream of the transcriptional start site suffices for most of the transcriptional regulation of the IL-6 gene (Fig. 1). Within this sequence stretch several transcription factors find their specific recognition sites. In 5 to 3 direction, AP-1, CREB, C/EBP 3/NF-IL6, SP-1 and NF-kB can bind to the promoter followed by TATA and its TATA binding protein TBP. Most enhancer factors become active in response to one or several different stimuli and the active factors can trigger transcription individually or in concert. For example, AP-1 is active upon cellular stress, or upon stimuli that tell cells to proliferate CREB becomes also active if cells experience growth signals, but also upon elevation of intracellular levels of cyclic adenosine monophosphate (cAMP), which occurs upon stimulation if so called hormone-activated G protein-coupled receptors. 

Instead of activating transcription the cortisol-induced GR represses IL-6 synthesis and, even more surprisingly, repression does not involve the GRE elements, but rather the kB site (Fig. 1). It appeals that of a monomeric GR protein without itself touching the DNA interacts with the RelA component of NF-kB [3]. As a result GR blocks the action of NF-kB. The negative interference by this crosstalk is not restricted to NF-kB, it occurs also with AP-1 and CREB, and with several other transcription factors not relevant for IL-6 expression. A nuclear isoform of the LIM protein Trip6 mediates the interaction between these factors and is required for the inhibitory GR function. This interesting negative crosstalk is part of the immune-suppressive action of cortisol. 

---