Concomitant down-regulation of expression of integrin subunits by N-myc in human neuroblastoma cells: differential regulation of alpha2, alpha3 and beta1.
Amplification and over-expression of the N-myc oncogene is associated with the progression of neuroblastoma in children and in a nude mouse model system. Neuroblastoma cell lines with widely different levels of N-myc illustrate an inverse relationship between N-myc over-expression and reduced expression of several integrin extracellular matrix receptors. Transfection and over-expression of N-myc in a neuroblastoma cell line not normally expressing the protein resulted in cells that grew loosely associated with tissue culture plates; this correlated with reduced levels of beta1 integrin subunit. Evidence is now presented that alpha2 and alpha3 integrin subunit levels are also reduced in cells that over-express N-myc, with virtually no association of alpha2 or alpha3 subunits with beta1. Consequently, maturation of the beta1 subunit and cell surface expression of the integrins are greatly reduced in N-myc-transfected cells. A small amount of beta1 protein does get to the cell surface, however, suggesting that an as yet unidentified alpha subunit is produced by the N-myc-expressing cells. Finally, the observed reductions in integrin protein levels are reflections of greatly reduced levels of integrin alpha2 and alpha3 mRNAs, as well as a smaller reduction in beta1 mRNA (80%, 94% and 52%, respectively). Post-transcriptional mechanisms modulating beta1 integrin levels are also operative. These results indicate that over-expression of N-myc from a transfected gene in a neuroblastoma cell line that does not normally produce the protein generates cell lines with many of the characteristics of naturally metastatic cells with amplified N-myc genes. Modulation of N-myc and integrin expressions may play a significant role in progression of human neuroblastoma.
Judware
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R
Case Western Reserve University, School of Medicine, Department of Molecular Biology and Microbiology, Cleveland, Ohio 44106, USA.
Culp
L A
LA
D015703:Antigens, CD / Q000235:genetics*; D015536:Down-Regulation; D016259:Genes, myc; D006801:Humans; D039421:Integrin alpha2; D039422:Integrin alpha3; D019012:Integrin beta1 / Q000235:genetics*; D016023:Integrins / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D039421:Integrin alpha2; D039422:Integrin alpha3; D019012:Integrin beta1; D016023:Integrins; D012333:RNA, Messenger