Loss of one HuD allele on chromosome #1p selects for amplification of the N-myc proto-oncogene in human neuroblastoma cells.
In human neuroblastoma tumors, amplification of the N-myc proto-oncogene and loss of all or part of the short arm of chromosome #1 are both associated with a poor prognosis. Accruing evidence indicates that it is the absence of one allele of the HuD (ELAVL4) gene, encoding the neuronal-specific RNA-binding protein HuD and localized to 1p34, that is linked to amplification. In 12 human neuroblastoma cell lines, N-myc amplification correlates with loss of one HuD allele and decreased HuD expression. Transfection experiments demonstrate that modulating HuD expression affects N-myc gene copy number as well as expression. Introduction of a sense HuD construct into two N-myc amplified cell lines considerably increases N-myc expression whereas gene copy number decreases. Conversely, expression of antisense HuD in N-myc nonamplified SH-SY5Y cells reduces HuD and N-myc mRNA levels even as cells show amplification of the N-myc gene. Thus, N-myc gene copy number is modulated by alteration of HuD expression. We propose that haploinsufficiency of HuD due to chromosome #1p deletion in neuroblastoma selects for cells that amplify N-myc genes. Application of these findings could lead to more effective therapies in the treatment of those patients with the worst prognosis.
Grandinetti
K B
KB
Laboratory of Neurobiology, Department of Biological Sciences, Fordham University, Bronx, NY 10458, USA.
Spengler
B A
BA
Biedler
J L
JL
Ross
R A
RA
D000483:Alleles; D001483:Base Sequence; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1; D017931:DNA Primers; D051959:ELAV Proteins / Q000235:genetics*; D000067779:ELAV-Like Protein 4; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D014162:Transfection
D017931:DNA Primers; D051959:ELAV Proteins; D000067779:ELAV-Like Protein 4; C498010:ELAVL4 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger