Agriculture Reference
In-Depth Information
about 220 kDa, which after intracellular proteolytic processing produces a mature
enzyme with a molecular mass of approximately 160 kDa. The exact mechanism
of regulation of lactase-phlorizin hydrolase processing is obscure. The rate of pro-
cessing of lactase-phlorizin hydrolase is accelerated by thyroid hormone, insulin,
cortisol, and insulin-like growth factors (Shulman et al. 1992; Dudley et al. 1996,
1998; Burrin et al. 2001). However, its expression has been seen in cultured epithelial
cells in the absence of hormonal stimuli (Kendall, Jumawan, and Koldovsky 1979;
Simon-Assmann et al. 1986). After weaning, in most humans the lactase-phloriz-
inase activity decreases to values of less than 10% of those observed during infancy
(Montgomery et al. 1991; Wang et al. 1998).
Genetic
cis
-regulation of lactase-phlorizin hydrolase transcription is mediated by
its promoter region (Boudreau et al. 2001; Troelsen et al. 2003) as well as by diverse
upstream sequences that bind transcription factors such as NF-LPH1 (Troelsen et al.
1992; Boudreau et al. 2002), GATA factors, hepatocyte nuclear factor HNF-1a, and
homeodomain protein Cdx-2 (Spodsberg et al. 1999; Krasinski et al. 2001). In addi-
tion, single-nucleotide polymorphisms located at positions −13910 (
C
/T) and −22018
(
G
/A) from the start codon have been associated with the phenotype of persistent
lactasia. These locations seem to be transcriptional enhancer sequences that activate
the LPH promoter.
s
u C r a s e
-i
s o m a L t a s e
The SI gene is located on human chromosome 3 (Chantret et al. 1992). SI is syn-
thesized as a single membrane protein 1827 amino acids long with a molecular
size close to 210 kDa; it is inserted in the membrane of the enterocytes through its
N-terminus (Sigrist et al. 1975; Hunziker et al. 1986) and subjected to intracellular
glycosylation (Danielsen 1982). Once transported to the apical membrane, it is sub-
jected to extracellular processing by pancreatic proteolytic enzymes generating a
free C-terminal sucrase subunit and a membrane-bound N-terminal isomaltase sub-
unit, which remain associated through noncovalent interactions (Cowell et al. 1986;
Hu, Spiess, and Semenza 1987; Saphiro et al. 1991).
The SI activity is tightly linked to enterocyte differentiation and responds to simi-
lar transcription factors as the lactase-phlorizin hydrolase promoter (Cdx-2, HNF-1a,
and GATA factors) (Wu et al. 1994; Taylor et al. 1997; Lynch et al. 2000; Silberg
et al. 2000; Boudreau et al. 2002). Several major regulatory target sequences for
the binding of these and other factors have been located upstream of the SI pro-
moter, directing the cell-line-specific transcription of the gene. SI footprints (i.e.,
SIF1, SIF2, and SIF3) are regulatory elements of the SI gene promoter that bind the
transcription factors Cdx-1 and Cdx-2 caudal-related proteins, HNF-1a, GATA-4,
and GATA-6, playing important roles in the regulation of the tissue-specific gene
expressions (Wu et al. 1994; Taylor et al. 1997; Lynch et al. 2000; Silberg et al. 2000;
Boudreau et al. 2002).
Transport of SI molecules to the apical membrane requires its correct intracel-
lular processing and, apparently, recognition by transporter systems. Diverse muta-
tions affecting signals required for processing and transport have been described
and appear to be the main causative factor of SI genetic deficiencies in humans
