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Minichromosome Maintenance Protein MCM7 Is a Direct Target of the MYCN Transcription Factor in Neuroblastoma¹

Departments of Pediatrics [J. M. S., S. E. P., M. K. B.], Pathology [M. J. H.], Molecular and Human Genetics [S-Y. C.], and The DeBakey Department of Surgery [S. M. B., J. G. N.], Baylor College of Medicine, Houston, Texas 77030; The Center for Cell and Gene Therapy, Houston, Texas 77030 [J. M. S., S-Y. C., M. K. B., J. G. N.]; Texas Children’s Cancer Center, Texas Children’s Hospital, Houston, Texas 77030 [S. S.]; and Incyte Genomics, Palo Alto, California 94304 [S. S.]

The MYCN oncogene is amplified in 25% of neuroblastoma tumors and is the most significant negative prognostic factor. The direct transcriptional targets of MYCN in MYCN-amplified tumors have not been defined. Microarray analysis of RNA from neuroblastoma primary cell cultures revealed 10-fold higher MCM7 expression in MYCN-amplified versus nonamplified tumors. MCM7 is an essential component of DNA replication licensing factor, a hexameric protein complex that regulates DNA synthesis during the cell cycle, preventing rereplication and ensuring maintenance of DNA euploidy. Additional experiments demonstrated markedly increased expression of MCM7 RNA and protein in MYCN-amplified neuroblastoma tumors and cell lines. Induction of MYCN in conditional cell lines results in increased expression of endogenous MCM7 mRNA and a 3-fold increase in protein levels. In addition, luciferase activity from MCM7 promoter/luciferase gene reporter constructs was significantly increased under MYCN-induced conditions. Specific electrophoretic mobility shifts of MCM7 promoter sequences are detected in extracts of MYCN-amplified cells. These findings demonstrate that in neuroblastoma, the MYCN oncogene directly activates genes required for DNA replication, and this may contribute to neoplastic transformation of these MYCN-amplified tumors.

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