Biomedical Engineering Reference
In-Depth Information
(N-acetylated-a-linked acidic dipeptidase) was coined and sometimes is still
used in the literature. More recently, the same enzyme was also shown to
possess folate hydrolase activity. It cleaves g-linked glutamates from folyl-
poly-g-glutamates, thus participating in the absorption of dietary folates
in the small intestine.
3
This observation led to the designation of the enzyme
as FOLH1. All of the names for the enzyme are still in use, which has
proved somewhat confusing. In fact, it took researchers some time to realize
that GCPII, NAALADase, FOLH1, and PSMA are in fact different names
for the same protein. We will refer to this protein as GCPII throughout
the chapter.
The physiological function of GCPII in healthy prostate is unknown, yet it is
well established that GCPII expression levels are elevated in prostate carci-
noma. Since prostate cancer accounts for the highest percentage (25% in 2009,
http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/
index-) of all incident cancer cases in American men and is the third leading
cause of cancer-related death, new diagnostic and therapeutic approaches
are being actively pursued. No physiological substrate for GCPII has been
identified in prostate tissue, and the protein's potential role in cancer growth
might not be associated with its enzymatic activity. GCPII expression has
also been described in the cancer-associated neovasculature of most solid
tumors.
4,5
The second major site of GCPII expression and activity is the nervous
system. GCPII is expressed in the plasma membrane of astrocytes and Schwann
cells.
6,7
The specific substrate of GCPII in the brain, NAAG, is an agonist of
metabotropic glutamate receptor 3.
8,9
GCPII inhibition leads to an increase in
NAAG concentration and has been shown to be neuroprotective in animal
models of ischemic brain injury
10,11
or traumatic brain injury,
12
to attenuate
neuropathic pain,
13
and to prolong survival of experimental animals in a mouse
model of amyotrophic lateral sclerosis.
14,15
GCPII is therefore a potential drug target for treatment of prostate cancer
and nervous system-related disorders. GCPII may also have applications for
cancer diagnostics and imaging.
3.2 Gene and mRNA
The GCPII gene, denoted as FOLH1, spans 62 035 base pairs and consists of 19
exon and 18 intron regions.
16
A number of alternative splice variants of GCPII
have been reported (for more details, see Section 3.2.1.1). FOLH1 is localized
on the 11th chromosome at position 11p11.2.
16,17
GCPII expression is androgen-responsive, i.e. androgen deprivation therapy
increases GCPII expression levels.
18
The GCPII enhancer, PSME, which is
found in the third intron of the FOLH1 gene, provides androgen regulation and
contributes to tissue specificity.
19
GCPII expression is also upregulated in
angiogenesis, leading to the hypothesis that a proangiogenic factor might be
responsible for regulation of GCPII expression.
