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

Shuichi Fujioka,1,2,{dagger} Jiangong Niu,1,3,{dagger} 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. Chiao1,2,3*

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 {kappa}B (NF-{kappa}B) and activator protein 1 (AP-1) transcription factors regulate many important biological and pathological processes. Activation of NF-{kappa}B is regulated by the inducible phosphorylation of NF-{kappa}B inhibitor I{kappa}B by I{kappa}B 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-{kappa}B and AP-1 may modulate each other, thus expanding the scope of these two rapidly inducible transcription factors. To determine whether NF-{kappa}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/I{kappa}B{alpha}M 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-{kappa}B downstream target genes. Inhibition of NF-{kappa}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-{kappa}B in participating in the regulation of elk-1, c-fos, and VEGF expression.


* Corresponding author. Mailing address: Department of Molecular & Cellular Oncology and Department of Surgical Oncology, Box 107, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: (713) 794-1030. Fax: (713) 794-4830. E-mail: pjchiao{at}mdanderson.org.

{dagger} S.F. and J.N. contributed equally to this study.


Molecular and Cellular Biology, September 2004, p. 7806-7819, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7806-7819.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.




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