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 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.
Mesh Terms:
Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Transcription Factors, Binding Sites, Cell Line, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney, Nerve Tissue Proteins, Nuclear Proteins, Protein Binding, Protein Structure, Tertiary, Repressor Proteins, Transcription, Genetic, Transcriptional Activation
Aryl Hydrocarbon Receptor Nuclear Translocator, Basic Helix-Loop-Helix Transcription Factors, Binding Sites, Cell Line, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney, Nerve Tissue Proteins, Nuclear Proteins, Protein Binding, Protein Structure, Tertiary, Repressor Proteins, Transcription, Genetic, Transcriptional Activation
Biochem. Biophys. Res. Commun.
Date: Nov. 09, 2007
PubMed ID: 17826745
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