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Transcriptional mechanisms of drug addiction.

Nestler EJ - Clin Psychopharmacol Neurosci (2012)

Bottom Line: Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state.Here we review the growing evidence for the role played by several prominent transcription factors, including a Fos family protein (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB), among several others, in drug addiction.As will be seen, each factor displays very different regulation by drugs of abuse within the brain's reward circuitry, and in turn mediates distinct aspects of the addiction phenotype.

View Article: PubMed Central - PubMed

Affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, USA.

ABSTRACT
Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state. Numerous transcription factors, proteins that bind to regulatory regions of specific genes and thereby control levels of their expression, have been implicated in the addiction process over the past decade or two. Here we review the growing evidence for the role played by several prominent transcription factors, including a Fos family protein (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB), among several others, in drug addiction. As will be seen, each factor displays very different regulation by drugs of abuse within the brain's reward circuitry, and in turn mediates distinct aspects of the addiction phenotype. Current efforts are geared toward understanding the range of target genes through which these transcription factors produce their functional effects and the underlying molecular mechanisms involved. This work promises to reveal fundamentally new insight into the molecular basis of addiction, which will contribute to improved diagnostic tests and therapeutics for addictive disorders.

No MeSH data available.


Related in: MedlinePlus

Epigenetic mechanisms of ΔFosB action. The figure illustrates the very different consequences when ΔFosB binds to a gene that it activates (e.g., Cdk5) versus represses (e.g., c-Fos). At the Cdk5 promoter (A), ΔFosB recruits histone acetyltransferases (HAT) and chromatin remodeling proteins (e.g., SWI-SNF factors), which promote gene activation. There is also evidence for exclusion of histone deacetylases (HDAC). In contrast, at the c-Fos promoter (B), ΔFosB recruits HDACs as well as histone methytransferases (HMT), which repress gene expression. A, P, and M depict histone acetylation, phosphorylation, and methylation, respectively.
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Figure 3: Epigenetic mechanisms of ΔFosB action. The figure illustrates the very different consequences when ΔFosB binds to a gene that it activates (e.g., Cdk5) versus represses (e.g., c-Fos). At the Cdk5 promoter (A), ΔFosB recruits histone acetyltransferases (HAT) and chromatin remodeling proteins (e.g., SWI-SNF factors), which promote gene activation. There is also evidence for exclusion of histone deacetylases (HDAC). In contrast, at the c-Fos promoter (B), ΔFosB recruits HDACs as well as histone methytransferases (HMT), which repress gene expression. A, P, and M depict histone acetylation, phosphorylation, and methylation, respectively.

Mentions: The other major goal of future research is to delineate the precise molecular steps by which these various transcription factors regulate their target genes. Thus, we now know that transcription factors control gene expression by recruiting to their target genes a series of co-activator or co-repressor proteins which together regulate the structure of chromatin around the genes and the subsequent recruitment of the RNA polymerase II complex which catalyzes transcription.4) For example, recent research has demonstrated that the ability of ΔFosB to induce the cdk5 gene occurs in concert with the recruitment of a histone acetyltransferase and related chromatin remodeling proteins to the gene.55) In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase (Fig. 3).2,9,31) Given that hundreds of chromatin regulatory proteins are likely recruited to a gene in concert with its activation or repression, this work is just the tip of the iceberg of vast amounts of information that need to be discovered in the years ahead.


Transcriptional mechanisms of drug addiction.

Nestler EJ - Clin Psychopharmacol Neurosci (2012)

Epigenetic mechanisms of ΔFosB action. The figure illustrates the very different consequences when ΔFosB binds to a gene that it activates (e.g., Cdk5) versus represses (e.g., c-Fos). At the Cdk5 promoter (A), ΔFosB recruits histone acetyltransferases (HAT) and chromatin remodeling proteins (e.g., SWI-SNF factors), which promote gene activation. There is also evidence for exclusion of histone deacetylases (HDAC). In contrast, at the c-Fos promoter (B), ΔFosB recruits HDACs as well as histone methytransferases (HMT), which repress gene expression. A, P, and M depict histone acetylation, phosphorylation, and methylation, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC3569166&req=5

Figure 3: Epigenetic mechanisms of ΔFosB action. The figure illustrates the very different consequences when ΔFosB binds to a gene that it activates (e.g., Cdk5) versus represses (e.g., c-Fos). At the Cdk5 promoter (A), ΔFosB recruits histone acetyltransferases (HAT) and chromatin remodeling proteins (e.g., SWI-SNF factors), which promote gene activation. There is also evidence for exclusion of histone deacetylases (HDAC). In contrast, at the c-Fos promoter (B), ΔFosB recruits HDACs as well as histone methytransferases (HMT), which repress gene expression. A, P, and M depict histone acetylation, phosphorylation, and methylation, respectively.
Mentions: The other major goal of future research is to delineate the precise molecular steps by which these various transcription factors regulate their target genes. Thus, we now know that transcription factors control gene expression by recruiting to their target genes a series of co-activator or co-repressor proteins which together regulate the structure of chromatin around the genes and the subsequent recruitment of the RNA polymerase II complex which catalyzes transcription.4) For example, recent research has demonstrated that the ability of ΔFosB to induce the cdk5 gene occurs in concert with the recruitment of a histone acetyltransferase and related chromatin remodeling proteins to the gene.55) In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase (Fig. 3).2,9,31) Given that hundreds of chromatin regulatory proteins are likely recruited to a gene in concert with its activation or repression, this work is just the tip of the iceberg of vast amounts of information that need to be discovered in the years ahead.

Bottom Line: Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state.Here we review the growing evidence for the role played by several prominent transcription factors, including a Fos family protein (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB), among several others, in drug addiction.As will be seen, each factor displays very different regulation by drugs of abuse within the brain's reward circuitry, and in turn mediates distinct aspects of the addiction phenotype.

View Article: PubMed Central - PubMed

Affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, USA.

ABSTRACT
Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state. Numerous transcription factors, proteins that bind to regulatory regions of specific genes and thereby control levels of their expression, have been implicated in the addiction process over the past decade or two. Here we review the growing evidence for the role played by several prominent transcription factors, including a Fos family protein (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB), among several others, in drug addiction. As will be seen, each factor displays very different regulation by drugs of abuse within the brain's reward circuitry, and in turn mediates distinct aspects of the addiction phenotype. Current efforts are geared toward understanding the range of target genes through which these transcription factors produce their functional effects and the underlying molecular mechanisms involved. This work promises to reveal fundamentally new insight into the molecular basis of addiction, which will contribute to improved diagnostic tests and therapeutics for addictive disorders.

No MeSH data available.


Related in: MedlinePlus