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Journal of Virology, January 2009, p. 651-661, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01538-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Induction of Neuronal and Tumor-Related Genes by Adenovirus Type 12 E1A {triangledown}

Hancheng Guan,1 Jim F. Williams,2 and Robert P. Ricciardi1,3*

Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104,1 Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213,2 Abramson Cancer Center, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 191043

Received 21 July 2008/ Accepted 21 October 2008

Adenovirus type 12 (Ad12) E1A protein (E1A-12) contains a unique 20-amino-acid spacer region between the second and third conserved regions. Substitution of a single amino acid in the spacer is able to abrogate Ad12 tumorigenesis. To investigate the function of the spacer, microarray analysis was performed on cells transformed by tumorigenic and nontumorigenic Ad12s that differ only by one amino acid in the spacer. Fewer than 0.8% of approximately 8,000 genes in the microarray exhibited differential expression of threefold and higher. Of these, more than half of the known genes with higher expression in the wild-type Ad12-transformed cells have neuronal-specific functions. Some of the other differentially expressed genes are involved in the regulation of the cell cycle, transcription, cell structure, and tumor invasiveness. Northern blot analyses of a subset of the neuronal genes, including Robo1, N-MYC, and {alpha}-internexin, confirmed their strong expression in multiple Ad12 tumorigenic cell lines. In contrast, these neuronal genes displayed only minor or negligible expression in cells transformed by spacer-mutated Ad12. Significantly, stable introduction of E1A-12 into nontumorigenic Ad5-transformed cells induced neuronal gene expression. We found that the neuron-restrictive silencer factor, which serves as a master repressor of neuronal genes, was inactivated in both Ad12- and Ad5-transformed cells via cytoplasmic retention, though only Ad12-transformed cells exhibited neuronal gene induction. Mutational analyses of the {alpha}-internexin promoter demonstrated that E1A-12-mediated neuronal gene induction further required the activation of neuronal promoter E-box elements. These results indicate that the spacer is involved in mediating neuronal and tumor-related genes.

* Corresponding author. Mailing address: University of Pennsylvania, Levy Research Building, Room 221, 4010 Locust Street, Philadelphia, PA 19104. Phone: (215) 898-3905. Fax: (215) 898-8385. E-mail: ricciardi{at}biochem.dental.upenn.edu

{triangledown} Published ahead of print on 5 November 2008.

Journal of Virology, January 2009, p. 651-661, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01538-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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