Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.21.73 (
urokinase-type plasminogen activator
)
10,685
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Bikunin, a Kunitz-type protease inhibitor, could potentially suppress tumor cell invasion and metastasis. Our previous study revealed that overexpression of bikunin in a human ovarian cancer cell line, HRA, resulted in a down-regulation in
uPA
and uPAR gene expression. For identifying the full repertoire of bikunin-regulated genes, a cDNA microarray hybridization screening was conducted using mRNA from bikunin-treated or bikunin-transfected HRA cells. A number of bikunin-regulated genes were identified, and their regulation was confirmed by Northern blot analysis. Our screen identified 11 bikunin-stimulated genes and 29 bikunin-repressed genes. The identified genes can indeed be classified into distinct subsets. These include transcriptional regulators, oncogenes/tumor suppressor genes, signaling molecules, growth/cell cycle, invasion/metastasis, cytokines, apoptosis, ion channels, extracellular matrix proteins, as well as some proteases. This screen identified suppression of several genes such as CDC-like kinase, LIM domain binding, Ets domain transcription factor, Rho GTPase-activating protein, tyrosine phosphorylation-regulated kinase, hyaluronan-binding protein, matriptase, and
pregnancy-associated plasma protein-A
(
PAPP-A
), which have previously been implicated in enhancing tumor promotion. Northern blot analysis confirmed that several genes including matriptase and
PAPP-A
were down-regulated by bikunin by approximately 9-fold. Further, genetic inhibition of matriptase or
PAPP-A
could lead to diminished invasion. These results show that bikunin alters the pattern of gene expression in HRA cells leading to a block in cell invasion.
...
PMID:Bikunin target genes in ovarian cancer cells identified by microarray analysis. 1257 Dec 29
A Kunitz-type protease inhibitor, bikunin, downregulates expression of
uPA
and its receptor uPAR at the mRNA and protein levels in several types of tumor cells. Our recent work showed that, using a cDNA microarray analysis,
pregnancy-associated plasma protein-A
(
PAPP-A
) is a candidate bikunin target gene. To clarify how reduced levels of
PAPP-A
may confer repressed invasiveness, we transfected human ovarian cancer cell line HRA with antisense (AS)-
PAPP-A
cDNA and compared the properties of the transfected cells to those of parental HRA cells. Here, we show that regulation of
uPA
mRNA and protein by IGF-I depends on the PI3K and MAPK signaling pathways and phosphorylation of Akt and ERK1/2 is required for IGF-I-mediated cell invasion; that IGFBP-4 protease in HRA cells is identified as
PAPP-A
; that reduced
PAPP-A
expression is associated with the upregulation of IGFBP-4 expression; that higher intact IGFBP-4 levels were associated with low invasive potential and growth rate in AS-
PAPP-A
cells in response to IGF-I; that IGF-I stimulates Akt and ERK1/2 activation of both the control and antisense cells, but the relative potency and efficacy of IGF-I were lower in the antisense cells compared to the control; and that genetic downregulation of
PAPP-A
reduces the proliferation, invasion and metastasis of HRA cells. In conclusion, our data identify a novel role for
PAPP-A
as a bikunin target gene. IGF-I-induced IGFBP-4 proteolysis by
PAPP-A
may enhance cell growth and invasion through IGF-I-dependent Akt and ERK1/2 activation and subsequently upregulation of
uPA
.
...
PMID:Genetic downregulation of pregnancy-associated plasma protein-A (PAPP-A) by bikunin reduces IGF-I-dependent Akt and ERK1/2 activation and subsequently reduces ovarian cancer cell growth, invasion and metastasis. 1496 70
