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J. Biol. Chem., Vol. 279, Issue 27, 27994-27999, July 2, 2004

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Nestin Is a Potential Mediator of Malignancy in Human Neuroblastoma Cells^*

Sharon K. Thomas, Conrad A. Messam¶, Barbara A. Spengler, June L. Biedler, and Robert A. Ross||

From the Laboratory of Neurobiology, Department of Biological Sciences, Fordham University, Bronx, New York 10458 and the ^¶Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Amplification of the N-myc proto-oncogene signifies aggressive behavior in human neuroblastoma. Likewise, overexpression of the intermediate filament nestin, a neuroectodermal stem cell marker, is linked to increased aggressiveness in several nervous system tumors. We investigated the interaction of these two proteins in human neuroblastoma cells. Neuroblastic cell variants with high levels of N-Myc protein have significantly higher nestin protein levels than non-amplified cell lines, suggesting that the transcription factor N-Myc may regulate nestin expression. Stable transfection of a nestin antisense sequence into neuroblastic, N-myc-amplified, LA1–55n cells results in a 2-fold reduction in nestin protein without altering N-Myc expression. However, cell functions attributed to N-Myc (growth rate, anchorage-independent growth, and motility) all decrease significantly. Transfection studies that modulate N-Myc levels also result in commensurate changes in nestin mRNA and protein amounts as well as in cell proliferation and motility. Thus, nestin appears to be downstream of and regulated by N-Myc. Gel mobility shift assays show that N-Myc binds specifically to E-box sequences in the regulatory second intron of the nestin gene and nuclear run-off studies show that increases in N-Myc protein up-regulate nestin transcription rate. Subcellular fractionation and immunoblot studies indicate that nestin is present in the nucleus as well as in the cytoplasm of neuroblastoma cell lines. Finally, DNA cross-linking experiments show that nestin binds DNA in N-myc-amplified N-type cell lines. Thus, nestin may be one mediator of N-myc-associated tumor aggressiveness of human neuroblastoma.

Received for publication, November 19, 2003 , and in revised form, April 23, 2004.

^* This research was supported by NCI, National Institutes of Health Grant CA77593 and the GRATIS Fund (to R. A. R.). 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.

Present address: Dept. of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461.

^|| To whom correspondence should be addressed: Dept. of Biological Sciences, Fordham University, 441 East Fordham Rd., Bronx, NY 10458. Tel.: 718-817-3654; Fax: 718-817-3616; E-mail: rross{at}fordham.edu.

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