Separate necdin domains bind ARNT2 and HIF1alpha and repress transcription

PWS is caused by the loss of expression of a set of maternally imprinted genes including NECDIN (NDN). NDN is expressed in post-mitotic neurons and plays an essential role in PWS as mouse models lacking only the Ndn gene mimic aspects of this disease. Patients haploid for SIM1 develop a PW-like synd...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2007-11, Vol.363 (1), p.113-118
Main Authors: Friedman, Eitan R, Fan, Chen-Ming
Format: Article
Language:English
Subjects:
Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism
Basic Helix-Loop-Helix Transcription Factors
Binding Sites
Cell Line
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Kidney - metabolism
Nerve Tissue Proteins - metabolism
Nuclear Proteins - metabolism
Protein Binding
Protein Structure, Tertiary
Repressor Proteins - metabolism
Transcription, Genetic - physiology
Transcriptional Activation - physiology
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Summary:PWS is caused by the loss of expression of a set of maternally imprinted genes including NECDIN (NDN). NDN is expressed in post-mitotic neurons and plays an essential role in PWS as mouse models lacking only the Ndn gene mimic aspects of this disease. Patients haploid for SIM1 develop a PW-like syndrome. Here, we report that NDN directly interacts with ARNT2, a bHLH-PAS protein and dimer partner for SIM1. We also found that NDN can interact with HIF1alpha. We showed that NDN can repress transcriptional activation mediated by ARNT2:SIM1 as well as ARNT2:HIF1alpha. The N-terminal 115 residues of NDN are sufficient for interaction with the bHLH domains of ARNT2 or HIF1alpha but not for transcriptional repression. Using GAL4-NDN fusion proteins, we determined that NDN possesses multiple repression domains. We thus propose that NDN regulates neuronal function and hypoxic response by regulating the activities of the ARNT2:SIM1 and ARNT2:HIF1alpha dimers, respectively.
ISSN:0006-291X