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J. Biol. Chem., Vol. 282, Issue 17, 12503-12516, April 27, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/17/12503    most recent M701450200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Beierle, E. A. Articles by Golubovskaya, V. M. Search for Related Content PubMed PubMed Citation Articles by Beierle, E. A. Articles by Golubovskaya, V. M. Social Bookmarking                      What's this?

N-MYC Regulates Focal Adhesion Kinase Expression in Human Neuroblastoma^*

Elizabeth A. Beierle¹, Angelica Trujillo, Abhilasha Nagaram, Elena V. Kurenova, Richard Finch, Xiaojie Ma, Jennifer Vella, William G. Cance, and Vita M. Golubovskaya²

From the Departments of Surgery and Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610

N-MYC is a transcription factor that plays an important role in cellular survival in neuroblastoma, and amplification of the N-MYC oncogene is the primary adverse prognostic indicator for neuroblastoma. Focal adhesion kinase (FAK) is a survival factor that has been shown to be overexpressed in many types of human cancers. In this study, we investigated the role of N-MYC regulation of FAK expression in neuroblastoma. We first found a correlation between N-MYC and FAK expression in neuroblastoma. Real time quantitative PCR demonstrated an increase in FAK mRNA abundance in the N-MYC-amplified IMR-32 compared with the nonamplified SK-N-AS neuroblastoma cell lines. FAK protein expression also correlated positively with N-MYC expression in the N-MYC-amplified IMR-32 versus nonamplified SK-N-AS neuroblastoma cell lines. The same results were seen with the isogenic N-MYC⁺ (Tet^–) and N-MYC^– (Tet⁺) neuroblastoma cell lines. Promoter-reporter assays showed that activity of the FAK promoter was increased in the N-MYC-amplified IMR-32 cell line, in the N-MYC-transfected SK-N-AS nonamplified cell line, and in the isogenic N-MYC⁺ (Tet^–) neuroblastoma cell lines compared with the nonamplified and N-MYC-nonexpressing cell lines. We also identified two N-MYC binding sites in the FAK promoter sequence and showed binding of N-MYC transcription factor to the FAK promoter through electrophoretic mobility shift, chromatin immunoprecipitation, and dual luciferase assays. Finally down-regulation of FAK expression in N-MYC-inducible neuroblastoma cell lines with FAK small interfering RNA or a dominant-negative FAK inhibitor (AdFAK-CD) significantly decreased viability and increased apoptosis in the N-MYC⁺ (Tet^–) cells compared with the isogenic N-MYC^– (Tet⁺) cells, demonstrating the biological significance of FAK overexpression in the N-MYC-expressing cell lines. This is the first report linking N-MYC and FAK in neuroblastoma, and it clearly demonstrates that N-MYC induces FAK expression. The results indicate that N-MYC regulation of FAK expression can control cellular functions in isogenic N-MYC^–/+ (Tet^+/–) neuroblastoma cell lines.

Received for publication, February 20, 2007

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Dept. of Surgery, University of Florida, P. O. Box 100286, JHMHSC, Gainesville, FL 32610-0286. Tel.: 352-392-3718; Fax: 352-392-9081; E-mail: beierea{at}surgery.ufl.edu. ² To whom correspondence may be addressed: Dept. of Surgery, University of Florida, P. O. Box 100286, JHMHSC, Gainesville, FL 32610-0286. Tel.: 352-273-8184; Fax: 352-392-0080; E-mail: golubvi{at}surgery.ufl.edu.

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