CONCOMITANT DOWN-REGULATION OF EXPRESSION OF INTEGRIN SUBUNITS BY N-MYC IN HUMAN NEUROBLASTOMA-CELLS - DIFFERENTIAL REGULATION OF ALPHA-2, ALPHA-3 AND BETA-1
R. Judware et La. Culp, CONCOMITANT DOWN-REGULATION OF EXPRESSION OF INTEGRIN SUBUNITS BY N-MYC IN HUMAN NEUROBLASTOMA-CELLS - DIFFERENTIAL REGULATION OF ALPHA-2, ALPHA-3 AND BETA-1, Oncogene, 14(11), 1997, pp. 1341-1350
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-expressio
n and reduced expression of several integrin extracellular matrix rece
ptors. Transfection and over-expression of N-myc in a neuroblastoma ce
ll line not normally expressing the protein resulted in cells that gre
w loosely associated with tissue culture plates; this correlated with
reduced levels of beta 1 integrin subunit. Evidence is now presented t
hat alpha 2 and alpha 3 integrin subunit levels are also reduced in ce
lls that over-express N-myc, with virtually no association of alpha 2
or alpha 3 subunits with beta 1. Consequently, maturation of the beta
1 subunit and cell surface expression of the integrins are greatly red
uced in N-myc-transfected cells. A small amount of beta 1 protein does
get to the cell surface, however, suggesting that an as yet unidentif
ied 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 alpha 2 and alpha 3 mRNAs, as well
as a smaller reduction in beta 1 mRNA (80%, 94% and 52%, respectively)
. Post-transcriptional mechanisms modulating beta 1 integrin levels ar
e also operative. These results indicate that over-expression of N-myc
from a transfected gene in a neuroblastoma cell line that does not no
rmally produce the protein generates cell lines with many of the chara
cteristics of naturally metastatic cells with amplified N-myc genes. M
odulation of N-myc and integrin expressions may play a significant rol
e in progression of human neuroblastoma.