Transcription CREB-mediated

CREB-mediated transcription are evident at the level of preinitiation complex recruitment. These data suggest a complexity of CREB-responsive gene expression that probably involves several co-regulators beyond the simple acetyltransferase mediators. 

The critical feature of CREB protein activation is phosphorylation, which is required for CREB-mediated stimulation of transcription [16]. PKA phosphorylates CREB on a serine positioned at amino acid 133 in the CREB protein sequence. How phosphorylation activates... 

Wayman, G. A., Impey, S., Marks, D., Saneyoshi, T., Grant, W. F., Derkach, V. and Soderling, T. R., 2006, Activity-Dependent Dendritic Arborization Mediated by CaM-Kinase I Activation and Enhanced CREB-Dependent Transcription of Wnt-2, Neuron, 50, pp 897-909. 

Gao J et al (2009) Inactivation of CREB mediated gene transcription by HDAC8 bound protein phosphatase. Biochem Biophys Res Commun 379(1) 1-5... 

Riccio A, Ahn S, Davenport CM et al (1999) Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 286 2358-2361... 

Riccio, A., et al. Mediation by a CREB Family Transcription Factor of NGF-Dependent Survival of Sympathetic Neurons. Sdence 286, 2358-2361 (1999). [How CREB may help protect neurons in times of stress.]... 

Figure 6 Potential antiapoptotic mechanisms mediated by nitric oxide. The nitrosation of Ras mediated by nitric oxide potentially leads to the activation of ERK1/2 or the PI3-kinase/AKT pathway, resulting in the suppression of proapoptotic proteins such as p53 and BAX or in the upregulation of antioxidant enzymes. Furthermore, Ras activation might mediate the phosphorylation/ activation of the cAMP response element binding protein (CREB), a transcription factor for Bcl-2, and the phosphorylation/inactivation of the proapoptotic protein BAD. In addition, the NO -mediated nitrosation of JNK and caspases may aiso contribute to the antiapoptotic properties of NO. ERK, extraceiiuiar signai-reguiated kinase PI3, phosphoinositoi 3-kinase JNK, c-Jun amino-terminai kinase.

In contrast, several lines of evidence suggest that the activation of the Ras-Raf-ERKl/2 pathway may oppose JNK-mediated effects with respect to mitochondria-dependent apoptosis (Fig. 4). ERKl/2 can phosphorylate and activate mitogen-and stress-activated kinase 1 (MSKl) and pp90 ribosomal S6 kinase (RSK) [83,84]. RSK can phosphorylate BAD, thereby inhibiting its proapoptotic effects [83]. Furthermore, both RSK and MSKl are potent activators of cyclic adenosine monophosphate (cAMP) element binding protein (CREB), a transcription factor for Blc-2, and therefore important for cell survival [84]. The upregulation or overexpression of Bcl-2 has been reported to be associated with the inactivation of JNK [75,85]. Thus, ERKl/2 activation could ultimately lead to JNK inactivation. Finally, the activation of c-Ras has been shown to result in a suppression of Bax expression, via a mechanism that involved activation of both the ERKl/2 signaling cascade and the phosphatidylinositol-3 -kinase (PI-3)/Akt pathway [80]. 

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. 

Chromatin remodeling, transcription factor modification by various enzyme activities, and the communication between the nuclear receptors and the basal transcription apparatus are accomplished by protein-protein interactions with one or more of a class of coregulator molecules. The number of these coregulator molecules now exceeds 100, not counting species variations and splice variants. The first of these to be described was the CREB-binding protein, CBP. CBP, through an amino terminal domain, binds to phosphorylated serine 137 of CREB and mediates transactivation in response to cAMP. It thus is described as a coactivator. CBP and... 

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. 

The detailed mechanisms involved in CREB phosphorylation were first established for the cAMP pathway. A first messenger that increases cAMP concentrations leads to activation of PKA and to translocation of the free catalytic subunit of the protein kinase into the nucleus, where it phosphorylates CREB on serine 133. Such phosphorylation then promotes the binding of CREB to a CREB-binding protein (CBP). CBP, upon binding CREB, interacts directly with the RNA polymerase II complex, which mediates the initiation of transcription. In most cases, such interactions lead to the activation of transcription, although it is possible that the expression of some genes may be repressed. 

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