Abstract
A novel gene that is down-regulated in lungs of
T/ebp/Nkx2.1-null mouse embryos has been identified
using a suppressive-subtractive hybridization method. The gene product
is a secreted protein, forms a homodimer, and exhibits an amino acid
sequence similar to that seen in the uteroglobin/Clara cell secretory
protein family of proteins. This gene, designated Ugrp1
(uteroglobin-related protein 1), consists of three exons and two
introns and produces three transcripts by alternative splicing. The
Ugrp1 gene was localized by fluorescence in
situ hybridization to mouse chromosome 18 at region 18C-D; this
region is homologous with human 5q31-34, where one of the asthma
susceptibility genes has been assigned. UGRP1 mRNA is predominantly
expressed in the lung, with low levels of expression in the thyroid.
Expression in the lung is detectable as early as embryonic day
12.5 and increases markedly by embryonic day 16.5. In
T/ebp/Nkx2.1-null embryo lungs, UGRP1 expression was
significantly reduced as assessed by RT-PCR analysis. Cotransfection
assays using a T/EBP/NKX2.1 expression construct with
Ugrp1 promoter-luciferase reporter constructs confirmed
that T/EBP/NKX2.1 regulates Ugrp1 gene activity at the
transcriptional level. Thus, Ugrp1 is a downstream
target gene for the T/EBP/NKX2.1 homeodomain transcription factor.
Changes in UGRP1 mRNA levels in lungs from antigen-sensitized mice
suggest the possible involvement of UGRP1 in inflammation.