Published online 5 October 2004
Nucleic Acids Research, Vol. 32 No. 17 © Oxford University Press 2004; all rights reserved
Negative cross-talk between the human orphan nuclear receptor Nur77/NAK-1/TR3 and nuclear factor-
B
1 Novartis Institute for BioMedical Research, A-1235 Vienna, Austria and 2 Ludwig Boltzmann-Institute for Applied Cancer Research, Vienna, Austria
* To whom correspondence should be addressed. Tel: +43 1 86634 330; Fax: +43 1 86634 727; Email: Hanna.Harant{at}novartis.com
Received as resubmission July 25, 2004; Accepted September 10, 2004
The effect of orphan nuclear receptor Nur77 overexpression on activation of an interleukin-2 (IL-2) promoter–luciferase construct was analyzed in the human leukemic cell line Jurkat. Cotransfection of the IL-2 promoter construct together with the Nur77 expression plasmid resulted in a significant repression of IL-2 promoter activation compared to control cells. The repression by Nur77 requires the N-terminal activation function-1 domain. The repressive effect of Nur77 on IL-2 promoter activation is mediated through inhibition of the transcription factor complex nuclear factor-
B (NF-B), since blocking or alteration of the IL-2 NF-B binding sites resulted in abrogation of the repressive effect of Nur77. Moreover, further examination of a reporter gene construct containing multiple copies of the IL-2 CD28 response element (CD28RE) showed that Nur77 can inhibit transactivation mediated by the NF-B components p65 and c-Rel. However, no effect of Nur77 was seen on p65-mediated transactivation of a construct containing multiple NF-B binding sites of the HIV LTR. Our data suggest that Nur77 is able to block activation through NF-B when bound to low-affinity NF-B binding sites, such as those located in the IL-2 promoter.
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