Nuclear-cytosolic transport of COMMD1 regulates NF-kappaB and HIF-1 activity.
Copper metabolism MURR1 domain1 (COMMD1) is a novel inhibitor of the transcription factors NF-kappaB and HIF-1, which play important roles in inflammation and tumor growth, respectively. In this study, we identified two highly conserved nuclear export signals (NESs) in COMMD1 and revealed that these NESs were essential and sufficient to induce maximal nuclear export of COMMD1. Inhibition of CRM1-mediated nuclear export by Leptomycin B resulted in nuclear accumulation of COMMD1. In addition, low oxygen concentrations induced the active export of COMMD1 from the nucleus in a CRM1-dependent manner. Disruption of the NESs in COMMD1 increased the repression of COMMD1 in transcriptional activity of NF-kappaB and HIF-1. In conclusion, these data indicate that COMMD1 undergoes constitutive nucleocytoplasmic transport as a novel mechanism to regulate NF-kappaB and HIF-1 signaling.
Muller
Patricia A J
PA
Department of Metabolic and Endocrine Diseases, UMC Utrecht, Utrecht, The Netherlands.
van de Sluis
Bart
B
Groot
Arjan J
AJ
Verbeek
Dineke
D
Vonk
Willianne I M
WI
Maine
Gabriel N
GN
Burstein
Ezra
E
Wijmenga
Cisca
C
Vooijs
Marc
M
Reits
Eric
E
Klomp
Leo W J
LW
D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000378:metabolism*; D003300:Copper / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D049790:Nuclear Export Signals; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D005231:Fatty Acids, Unsaturated; D051793:Hypoxia-Inducible Factor 1; D016328:NF-kappa B; D049790:Nuclear Export Signals; D051996:Transcription Factor RelA; D014157:Transcription Factors; D003300:Copper; C038753:leptomycin B