CREB (Cyclic-AMP Response Element Binding) proteins are transcription factors which bind to certain sequences called CRE elements in DNA and thereby increase or decrease the transcription of certain genes. 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 cyclic_AMP 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 molecule then binds to a CRE element and thereby switches certain genes on or off.
CREB proteins in neurons are 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. Fruit flies genetically engineered to overexpress the activator form have been shown to learn significantly faster than wild-type flies: they readily form long-term memories after only a single training, while wild-type flies require several spaced repetitions.
In humans, abnormalities of the CREB protein gene CBP is associated with Rubenstein-Taybi syndrome.
These other proteins contain a domain of amino acid sequences that are homologous to a domain first identified in the c-Src proto-oncogene (c-designates the cellular form of proto-onogenes that were first identified in transforming retrovirus).
CEP-1347, an orally active molecule, is a selective and potent inhibitor of the stress-activated protein kinase pathway, an intracellular signaling pathway that is an essential component of the stress response leading to neuronal death.
Kinases are turned on or off by phosphorylation (sometimes by the kinase itself - cis-phosphorylation/autophosphorylation), by binding of activator proteins or inhibitor proteins, or small molecules, or by controlling their location in the cell relative to their substrates.
IL-1beta activates the p38 mitogen- activated protein kinase (MAPK) signaling pathway and induces the activation of CREB in hippocampal neurons, in contrast to the activation of NF-kappaB in hippocampal astrocytes, demonstrating cell type-specific signaling responses to IL-1 in the brain and yielding distinct functional responses.
Binding of VEGF to the KDR/Flk1 receptor tyrosine kinase induces phosphorylation of the CRE- bindingprotein (CREB) transcription factor on serine 133 and increases CREB DNAbinding and transactivation.
Binding activity was competed with unlabeled oligonucleotides that contained the junB CRE-like site or the somatostatin CRE consensus motif, the latter observation suggests that members of the activating transcription factor/CRE bindingprotein (CREB) family may mediate mIg-dependent junB transcription.
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