Regulation of Corepressor Function by Nuclear NADH

  title={Regulation of Corepressor Function by Nuclear NADH},
  author={Qinghong Zhang and David W. Piston and Richard H. Goodman},
  pages={1895 - 1897}
The corepressor CtBP (carboxyl-terminal binding protein) is involved in transcriptional pathways important for development, cell cycle regulation, and transformation. We demonstrate that CtBP binding to cellular and viral transcriptional repressors is regulated by the nicotinamide adenine dinucleotides NAD+ and NADH, with NADH being two to three orders of magnitude more effective. Levels of free nuclear nicotinamide adenine dinucleotides, determined using two-photon microscopy, correspond to… 
CtBP as a Redox Sensor in Transcriptional Repression
It is demonstrated that CtBP binding to transcription repressors is stimulated by NAD+ and NADH, with NADH being two to three orders of magnitude more effective, and suggest that the transcriptional corepressor CtBP may serve as a redox sensor to provide a link between gene expression and metabolism.
Transcription corepressor CtBP is an NAD(+)-regulated dehydrogenase.
NADH/NAD+ binding and linked tetrameric assembly of the oncogenic transcription factors CtBP1 and CtBP2
Biophysical techniques are applied to address fundamental issues of CtBP assembly and nucleotide binding affinity to unambiguously demonstrate that CtBP assembles into tetramers in the presence of saturating NAD+ or NADH with tetramer to dimer dissociation constants about 100 nm.
Structural Determinants of CtBP Function
The structural characteristics of the CtBP family of transcriptional corepressors suggest an additional role for coenzyme nicotinamide adenine dinudeotide in the repression of gene expression.
Differential binding of NAD+ and NADH allows the transcriptional corepressor carboxyl-terminal binding protein to serve as a metabolic sensor
The studies show a >100-fold higher affinity of NADH than NAD+, consistent with the proposed function of CtBP as a nuclear redox sensor, and support the possibility that changes in nuclear nicotinamide adenine dinucleotides could regulate the functions ofCtBP in cell differentiation, development, or transformation.
The CtBP2 co-repressor is regulated by NADH-dependent dimerization and possesses a novel N-terminal repression domain.
The functional characterization of CtBP is extended by demonstrating that amino acid substitutions at Gly189 in the conserved NAD+-binding fold both abrogate the ability ofCtBP2 to homodimerize and are associated with a dramatic loss of co-repressor activity.
CtBPs promote mitotic fidelity through their activities in the cell nucleus
It is demonstrated that it is the interaction of CtBPs with transcriptional regulators and/or chromatin-modifying enzymes in the cell nucleus, rather than their role in Golgi fission, which is critical for the maintenance of mitotic fidelity.
C-terminal binding proteins: central players in development and disease
Although recent efforts have characterized the essential involvement of CtBPs in promoting cellular survival, the dysregulation of Ct BPs in both neurodegenerative disease and cancers remains to be fully elucidated.


ZEB represses transcription through interaction with the corepressor CtBP.
  • A. PostigoD. Dean
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
It is demonstrated that ZEB and zfh-1 interact with the corepressor CtBP to repress transcription and that the interaction of CtBP with ZEB at the promoter is necessary for repressor activity.
The CtBP family: enigmatic and enzymatic transcriptional co‐repressors
  • J. TurnerM. Crossley
  • Biology
    BioEssays : news and reviews in molecular, cellular and developmental biology
  • 2001
Observations raise the possibility that CtBP proteins might regulate gene expression directly by means of their enzymatic activities, in addition to serving as simple bridging proteins.
Evidence for a function of CtBP in epithelial gene regulation and anoikis
The results indicate that E1a's interaction with CtBP activates at least three epithelial cell adhesion gene promoters, and implicate CtBP as an antagonist of the epithelial phenotype and anoikis, and indicate a new but undefined role for nuclear acetylases in maintaining the transformed phenotype.
The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases.
Discovery of an intrinsic deacetylation activity for the conserved SIR2 family provides a mechanism for modifying histones and other proteins to regulate transcription and diverse biological processes.
Control of the redox state of the nicotinamide-adenine dinucleotide couple in rat liver cytoplasm.
The results are discussed and taken to confirm that the order of magnitude of the value of the redox state of the cytoplasmic NAD couple in rat liver is controlled by the phosphorylationstate of the adenine nucleotide system.
The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver.
The bearing of these findings on various problems, including the number of NAD(+)-NADH pools in liver cells; the applicability of the method to tissues other than liver; the transhydrogenase activity of glutamate dehydrogenase; the physiological significance of the difference of the redox states of mitochondria and cytoplasm; aspects of the regulation of theredox state of cell compartments; the steady-state concentration of mitochondrial oxaloacetate.
Silent information regulator 2 family of NAD- dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose.
It is suggested that the reported histone/protein ADP-ribosyltransferase activity is a low-efficiency side reaction that can be explained through the partial uncoupling of the intrinsic deacetylation and acetate transfer to ADp-ribose.
A region in the C‐terminus of adenovirus 2/5 E1a protein is required for association with a cellular phosphoprotein and important for the negative modulation of T24‐ras mediated transformation, tumorigenesis and metastasis.
Results suggest that this 14 amino acid region of exon 2 of the adenovirus 2/5 E1A oncogene product, the 243R protein, may contain a function that is important for immortalization and negative modulation of tumorigenesis and metastasis.
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
The analysis of two SIR2 mutations supports the idea that this deacetylase activity accounts for silencing, recombination suppression and extension of life span in vivo, and provides a molecular framework of NAD-dependent histone de acetylation that connects metabolism, genomic silencing and ageing in yeast and, perhaps, in higher eukaryotes.
Separation of the glucose-stimulated cytoplasmic and mitochondrial NAD(P)H responses in pancreatic islet beta cells.
Two-photon excitation microscopy was used to image and quantify NAD(P)H autofluorescence from intact pancreatic islets under glucose stimulation, showing that the large mitochondrial change in glucose-stimulated NAD( P)H dominates the total signal but may depend on the smaller but more rapid cytoplasmic increase.