Project 1:  Role of CREB in Opiate and Cocaine Addiction
PI, Eric Nestler (Mount Sinai)

CREB (cAMP response element binding protein) was first identified as a cAMP-regulated transcription factor, which mediates many of the effects of cAMP on gene expression via specific CRE’s (cAMP response elements) present within the regulatory regions of many genes. cAMP activates CREB via protein kinase A (PKA), which phosphorylates CREB on Ser133. This phosphorylation enables CREB dimers, possibly already bound to CRE’s, to interact with CBP (CREB-binding protein), which is a histone acetyltransferase (HAT) which promotes gene expression in part by recruiting the basal RNA polymerase II transcription complex. We now know that several other kinases, including Ca2+/calmodulin-dependent kinase IV (CaMKIV) and growth factor-activated kinases (e.g., RSK) also phosphorylate CREB on the same serine residue, indicating that CREB activation represents a point of convergence for multiple signaling pathways within neurons. There is now considerable evidence that CREB, in different regions of the nervous system, is a key molecular mediator of many forms of neural and behavioral plasticity. Our Program Project Grant has demonstrated that CREB is key mediator of drug tolerance and dependence. Project 1 focuses on identifying target genes for CREB that mediate this effect.

Using ChIP-chip, we identified gene promoters that show enrichment of CREB binding in nucleus accumbens after chronic cocaine. Top shows that a subset of these genes also show cocaine-induced changes in histone acetylation or methylation. Bottom depicts CREB binding at two particular gene targets, prodynorphin (Pdyn) and WNT7a. More recently, we have turned to ChIP-Seq which provides more complete and accurate information. From Renthal et al., Neuron, 2009.

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