Regulation of corepressor function by nuclear NADH.
Qinghong Zhang1, David W Piston, Richard H Goodman
1Vollum Institute, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201, USA.
Science (New York, N.Y.)
|February 16, 2002
Summary
The carboxyl-terminal binding protein (CtBP) acts as a redox sensor, with its binding regulated by the NAD+/NADH ratio. This mechanism influences gene transcription, impacting cellular processes like development and cell cycle regulation.
Area of Science:
- Molecular Biology
- Biochemistry
- Cell Biology
Background:
- The carboxyl-terminal binding protein (CtBP) is a corepressor crucial for transcriptional regulation.
- CtBP plays roles in development, cell cycle control, and cellular transformation.
- The precise regulatory mechanisms of CtBP, particularly its interaction with transcriptional repressors, are not fully understood.
Purpose of the Study:
- To investigate the role of nicotinamide adenine dinucleotides (NAD+ and NADH) in regulating CtBP binding to transcriptional repressors.
- To determine the in vivo levels of nuclear NAD+/NADH and their correlation with CtBP activity.
- To explore the potential of CtBP as a cellular redox sensor.
Main Methods:
- Utilized two-photon microscopy to measure free nuclear NAD+/NADH levels.
- Assessed CtBP binding to cellular and viral repressors in response to varying NAD+/NADH concentrations.
- Investigated the effects of agents that modulate NADH levels on CtBP-mediated repression in vivo.
Main Results:
- CtBP binding to transcriptional repressors is modulated by NAD+ and NADH, with NADH being significantly more potent.
- Measured nuclear NAD+/NADH levels required for half-maximal CtBP binding are lower than previously reported.
- Increasing NADH levels in vivo enhances CtBP binding and potentiates CtBP-mediated transcriptional repression.
Conclusions:
- CtBP functions as a redox sensor, utilizing the NAD+/NADH ratio to regulate its interaction with transcriptional partners.
- The findings reveal a novel regulatory mechanism for CtBP, linking cellular redox state to transcriptional control.
- This provides insights into CtBP's role in fundamental cellular processes and disease states.
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