Small molecule screening identifies regulators of the transcription factor ΔfosB

Yun Wang, Teresa I. Cesena, Yoko Ohnishi, Rebecca Burger-Caplan, Vivian Lam, Paul D. Kirchhoff, Scott D. Larsen, Martha J. Larsen, Eric J. Nestler, Gabrielle Rudenko

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

δFosB protein accumulates in the striatum in response to chronic administration of drugs of abuse, L-DOPA, or stress, triggering long lasting neural and behavioral changes that underlie aspects of drug addiction, abnormal involuntary movements (dyskinesia), and depression. δFosB binds AP-1 DNA consensus sequences found in promoters of many genes and can both repress or activate gene transcription. In the striatum, ΔFosB is thought to dimerize with JunD to form a functional transcription factor, though strikingly JunD does not accumulate in parallel. One explanation is that δFosB can recruit different partners, including itself, depending on the neuron type in which it is induced and the chronic stimulus, generating protein complexes with different effects on gene transcription. To develop chemical probes to study ΔFosB, a high-throughput screen was carried out to identify small molecules that modulate ΔFosB function. Two compounds with low micromolar activity, termed C2 and C6, disrupt the binding of ΔFosB to DNA via different mechanisms, and in in vitro assays stimulate ΔFosB-mediated transcription. In cocaine-treated mice, C2 significantly elevates mRNA levels of the AMPA glutamate receptor GluR2 subunit with specificity, a known target gene of ΔFosB that plays a role in drug addiction and endogenous resilience mechanisms. C2 and C6 show different activities against ΔFosB homodimers compared to ΔFosB/JunD heterodimers, suggesting that these compounds can be used as probes to study the contribution of different ΔFosB-containing complexes on the regulation of gene transcription in biological systems and to assess the utility of ΔFosB as a therapeutic target.

Original languageEnglish (US)
Pages (from-to)546-556
Number of pages11
JournalACS Chemical Neuroscience
Volume3
Issue number7
DOIs
StatePublished - Jul 18 2012
Externally publishedYes

Fingerprint

Transcription
Screening
Transcription Factors
Genes
Dyskinesias
Molecules
Substance-Related Disorders
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
AMPA Receptors
DNA sequences
Transcription Factor AP-1
Consensus Sequence
Glutamate Receptors
Street Drugs
Biological systems
Cocaine
Pharmaceutical Preparations
Neurons
Assays
Proteins

Keywords

  • δFosB
  • depression
  • drug addiction
  • dyskinesia
  • high throughput screening
  • transcription factor

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Physiology
  • Cognitive Neuroscience

Cite this

Wang, Y., Cesena, T. I., Ohnishi, Y., Burger-Caplan, R., Lam, V., Kirchhoff, P. D., ... Rudenko, G. (2012). Small molecule screening identifies regulators of the transcription factor ΔfosB. ACS Chemical Neuroscience, 3(7), 546-556. https://doi.org/10.1021/cn3000235

Small molecule screening identifies regulators of the transcription factor ΔfosB. / Wang, Yun; Cesena, Teresa I.; Ohnishi, Yoko; Burger-Caplan, Rebecca; Lam, Vivian; Kirchhoff, Paul D.; Larsen, Scott D.; Larsen, Martha J.; Nestler, Eric J.; Rudenko, Gabrielle.

In: ACS Chemical Neuroscience, Vol. 3, No. 7, 18.07.2012, p. 546-556.

Research output: Contribution to journalArticle

Wang, Y, Cesena, TI, Ohnishi, Y, Burger-Caplan, R, Lam, V, Kirchhoff, PD, Larsen, SD, Larsen, MJ, Nestler, EJ & Rudenko, G 2012, 'Small molecule screening identifies regulators of the transcription factor ΔfosB', ACS Chemical Neuroscience, vol. 3, no. 7, pp. 546-556. https://doi.org/10.1021/cn3000235
Wang Y, Cesena TI, Ohnishi Y, Burger-Caplan R, Lam V, Kirchhoff PD et al. Small molecule screening identifies regulators of the transcription factor ΔfosB. ACS Chemical Neuroscience. 2012 Jul 18;3(7):546-556. https://doi.org/10.1021/cn3000235
Wang, Yun ; Cesena, Teresa I. ; Ohnishi, Yoko ; Burger-Caplan, Rebecca ; Lam, Vivian ; Kirchhoff, Paul D. ; Larsen, Scott D. ; Larsen, Martha J. ; Nestler, Eric J. ; Rudenko, Gabrielle. / Small molecule screening identifies regulators of the transcription factor ΔfosB. In: ACS Chemical Neuroscience. 2012 ; Vol. 3, No. 7. pp. 546-556.
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