The
VEGF
system is essential for angiogenesis.
VEGF
exerts its biological effects through two high affinity
receptors—
Fms-like tyrosine kinase 1 (flt-1)
receptor 1
(VEGFR-1) and
VEGF receptor-2
(VEGFR-2/FLK-1/KDR).
These VEGF receptors are found at the surface of
endothelial cells, hematopoietic stem cells, leukocytes,
osteoblasts as well as many tumor cells. VEGF
overexpression frequently correlates with increased
microvascularity, metastasis and with decreased
spontaneous apoptosis.
There is a general agreement that FLK-1 is the major
mediator of the mitogenic and angiogenic effects of VEGF
during transformation and tumorigenesis. However, recent
reports demonstrate that flt-1 is present and functional on
different human cancer cells, and that activation of flt-1
by VEGF can activate processes involved in tumor
progression and metastasis.Recent evidence indicates that
flt-1 is not only involved in lung-specific metastasis by
MMP9 induction, but is also involved in ligand-induced
pathological angiogenesis in tumor cells.
Levels of flt-1 expression can vary considerably across
tissues (e.g. lung, kidney, heart, liver, and brain) and in
response to stimuli (e.g. hypoxia). Given the association
of flt-1 function with cell growth, development and various
pathologies, variations in expression are expected to
contribute to its cellular impact.
Thus, addressing mechanisms that control Flt1 expression in
response to environmental stress is relevant to
understanding several diseases. Several studies suggest
that VEGF expression is negatively regulated by p53, a
master regulator and tumor suppressor. However, a precise
mechanism has not been established, There are no reports of
additional components of the VEGF signal transduction
pathway being part of the p53 transcriptional network.
In response to a variety of stress signals, such as DNA
damage, activated tumor suppressor p53 acts as a master
transcriptional regulator to directly control several
biological outcomes including growth arrest, apoptosis, DNA
repair, senescence and angiogenesis. The tumor suppressor
function of p53 is correlated with direct transcriptional
activation of promoters containing p53 REs.
Previously, we found that the tumor
suppressor p53 could stimulate transcription at a human
Flt1 promoter variant where a C>T single nucleotide
polymorphism (SNP) results in an apparent partial p53
response element (RE).
This mechanism is likely to be relevant to expression
control of other genes and expands the number of genes
that may be directly controlled in master regulatory
networks.
Therefor, we became interested to understand more
regulatory networks influencing flt-1 regulation. Again, we
started to study the influence the role of estrogens on
flt-1 regulation.
A polymorphism in the VEGFR1 promoter
reveals synergistic control of expression by p53 and
estrogen receptor acting at partial binding
sites.
Understanding the regulation of human gene expression
requires knowledge of what can be considered a “second
genetic code” that includes epigenetic effects, e.g.
methylation of promoter regions, and mostly forgotten the
binding specificities of transcription factors and the
combination of TF binding sites that constitute specific
enhancer elements.