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Molecular and Cellular Biology, September 2004, p. 7806-7819, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7806-7819.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

NF-B and AP-1 Connection: Mechanism of NF-B-Dependent Regulation of AP-1 Activity

Shuichi Fujioka,^1,2, Jiangong Niu,^1,3, Christian Schmidt,^1,2 Guido M. Sclabas,^1,4 Bailu Peng,^1,2 Tadashi Uwagawa,¹ Zhongkui Li,¹ Douglas B. Evans,¹ James L. Abbruzzese,⁵ and Paul J. Chiao^1,2,3*

Department of Surgical Oncology,¹ Department of Molecular and Cellular Oncology,² Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center,⁵ The Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas,³ Department of Visceral and Transplantation Surgery, Inselspital, University of Bern, Bern, Switzerland⁴

Received 8 March 2004/ Returned for modification 5 May 2004/ Accepted 17 May 2004

Nuclear factor B (NF-B) and activator protein 1 (AP-1) transcription factors regulate many important biological and pathological processes. Activation of NF-B is regulated by the inducible phosphorylation of NF-B inhibitor IB by IB kinase. In contrast, Fos, a key component of AP-1, is primarily transcriptionally regulated by serum responsive factors (SRFs) and ternary complex factors (TCFs). Despite these different regulatory mechanisms, there is an intriguing possibility that NF-B and AP-1 may modulate each other, thus expanding the scope of these two rapidly inducible transcription factors. To determine whether NF-B activity is involved in the regulation of fos expression in response to various stimuli, we analyzed activity of AP-1 and expression of fos, fosB, fra-1, fra-2, jun, junB, and junD, as well as AP-1 downstream target gene VEGF, using MDAPanc-28 and MDAPanc-28/IBM pancreatic tumor cells and wild-type, IKK1^–/–, and IKK2^–/– murine embryonic fibroblast cells. Our results show that elk-1, a member of TCFs, is one of the NF-B downstream target genes. Inhibition of NF-B activity greatly decreased expression of elk-1. Consequently, the reduced level of activated Elk-1 protein by extracellular signal-regulated kinase impeded constitutive, serum-, and superoxide-inducible c-fos expression. Thus, our study revealed a distinct and essential role of NF-B in participating in the regulation of elk-1, c-fos, and VEGF expression.

S.F. and J.N. contributed equally to this study.

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