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NIDA Proteomics Center
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Investigators
> Eric Nestler
Proteomic Analysis of ∆FosB, a
Molecular Switch for Addiction
Eric Nestler, Dept of Neuroscience, Mount Sinai School of Medicine
Drug addiction is associated with long-lasting
changes in gene expression, yet the molecular basis of this persistence has
remained unknown. Our laboratory has provided evidence that one unique mechanism
underlying the lasting effects of drugs of abuse on changes in gene expression
in the brain’s reward circuitry involves the Fos family transcription factor, ∆FosB.
We have shown that ∆FosB is induced in the nucleus accumbens and other key brain
reward regions in response to chronic administration of all classes of drugs of
abuse, but not in response to other, non-abused psychotropic drugs. Unlike all
other Fos family proteins, variants of ∆FosB are highly stable proteins. This
stability underlies the unique accumulation of ∆FosB after chronic drug
administration. Moreover, this stability also means that ∆FosB persists in brain
reward regions for a relatively prolonged period (weeks-months) after cessation
of drug exposure. In this way, regulation of ∆FosB provides a unique mechanism
by which drugs of abuse induce some of their lasting effects on gene expression.
Indeed, DNA microarray and ChIP-chip analyses have established that ∆FosB is an
important mediator of many of the effects of drugs of abuse on gene expression.
Importantly, ∆FosB regulates a partially distinct set of target genes in brain
reward regions compared to other Fos family proteins.
The goal of the proposed studies is to characterize the molecular basis of ∆FosB
action to better understand the biochemical mechanisms underlying its unique
stability and its unique transcriptional effects on target genes. With respect
to the former, we have demonstrated that phosphorylation of ∆FosB on Ser27 by
casein kinase 2 increases the protein’s stability in vitro and in vivo. We have
more recently seen phosphorylation of ∆FosB by several other proteins kinases
and are now interested in defining the specific sites involved and the effect of
these phosphorylation reactions on various functions of the protein. With
respect to the latter, we have evidence that ∆FosB may act in concert with
unique binding partners, which may explain its unique effects on gene
expression. Accordingly, we are interested in searching for proteins in brain
reward regions that bind to ∆FosB prerentially compared to other Fos family
proteins.
Together, these studies promise important advances in our understanding of the
molecular basis of addiction.
Drug addiction is a serious public health concern and is associated with
considerable loss of life, loss of productivity, and suffering to affecting
patients and their families. Addiction is a life-long condition, and is thought
to involve changes in the way that the genome functions. We propose to better
understand these mechanisms of gene regulation via advanced studies of the
drug-regulated transcription factor, ∆FosB. |
