New Evidence for an Extra-Hepatic Role of N-acetylglucosaminyltransferase III in the Progression of Diethylnitrosamine-induced Liver Tumors in Mice
2000
N -acetylglucosaminyltransferase III (GlcNAc-TIII) is encoded
by the Mgat3 gene and catalyzes the addition of the
bisecting GlcNAc to the core of N -glycans. Mice lacking
GlcNAc-TIII due to the insertion mutation
Mgat3 tm1Pst (termed
Mgat3 neo ), exhibit retarded progression of
liver tumors induced by diethylnitrosamine (DEN; M. Bhaumik
et al. , Cancer Res., 58: 2881–2887, 1998).
This phenotype seemed to be due to a reduction, in activity or amount,
of a circulating glycoprotein(s) that enhances DEN-induced liver tumor
progression. Here, we provide new evidence to support this hypothesis.
First, we show that mice with a deletion mutation of the
Mgat3 gene coding exon
( Mgat3 tmlJxm , termed
Mgat3 Δ ) also exhibit retarded progression of
DEN-induced liver tumors. At 7 months there was a significant decrease
in liver weight (∼27%; P < 0.01),
reflecting reduced tumor burden in Mgat3 Δ/Δ
mice. In addition, tumors were generally fewer and smaller, and
histological changes were less severe in
Mgat3 Δ/Δ livers. Therefore, tumor
progression is retarded in mice with two different null mutations in
the Mgat3 gene. Second, we show that the development of
DEN-induced tumors is unaltered by high levels of GlcNAc-TIII in the
liver of transgenic mice. The Mgat3 gene coding exon under
the control of the major urinary protein (MUP) promoter was used to
generate transgenic mice that express GlcNAc-TIII in liver. Following
DEN injection and phenobarbitol treatment, however, no significant
differences were observed between MUP/ Mgat3 transgenic and
control mice in either tumor numbers or liver weight. The combined data
provide strong evidence that retarded progression of tumors in mice
lacking GlcNAc-TIII is due to the absence of the bisecting GlcNAc
residue on N -glycans of a circulating glycoprotein(s) from
a tissue other than liver.
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