Natural Tumor Suppressor In Body
Discovered By Medical Researchers
By Sue Pondrom
A natural tumor
suppressor that could potentially be turned on in certain cancer
cells to prevent the formation of tumors has been discovered
by researchers at the UCSD School of Medicine.
Located on chromosome
18 and called PH domain Leucine-rich repeat Protein Phosphatase
(PHLPP, pronounced “flip”), the tumor suppressor
is described in the April 1, 2005 issue of the journal Molecular
Cell. The scientists demonstrated that PHLPP deletes a
phosphate molecule, causing termination of cell-growth signaling
by a protein called Akt that controls the balance between cell
growth leading to cancer and cell death that prevents tumor
kinase B controls the balance between cell survival and
cell death. The activated form of this kinase tips the balance
towards cell proliferation and survival, whereas the inactive
form tips the balance towards programmed cell death, apoptosis.
Akt can be inactivated by two mechanisms: the tumor suppressor
PTEN pre-empts activation by removing the activating signals,
and the tumor suppressor PHLPP terminates activation by
directly turning off a key phosphorylation switch on Akt.
“A drug that
turns on PHLPP, so that it suppresses cell growth caused by
Akt, could be a potential cancer therapy,” said the study’s
senior author, Alexandra C. Newton, Ph.D., UCSD professor of
pharmacology. “Currently there are no compounds identified
to directly stop Akt from causing cancer growth, once Akt signaling
has been initiated.”
Scientists have known
that Akt is critical in regulating cell growth and death, and
that it is linked to some of the most common human cancers.
Although one group of scientists discovered a molecule called
PTEN*, which prevents activation of Akt, no
one to date had determined how to directly turn off Akt once
it has been activated.
Since the Akt molecule
is locked in the “on” position when it has phosphate
on it, the UCSD team reasoned that there must be another molecule
that will strip off the phosphate and lock Akt in the “off”
position. The scientists conducted a database search of the
human genome for a phosphatase, which is an enzyme that acts
as a catalyst in regulating cellular processes by removing phosphate
molecules. Based on the chemical components of Akt, they specifically
looked for a phosphatase linked to the PH domain, a protein
module found in a wide variety of chemical signaling proteins
in organisms ranging from yeast to humans.
Once they found PHLPP,
which they discovered was expressed throughout the body, the
scientists used biochemical and cellular studies in human and
other mammalian tissue to determine that PHLPP levels are markedly
reduced in several colon cancer and gliobastoma human cell lines
that had elevated Akt phosphorylation. Reintroduction of PHLPP
into the cell lines caused a dramatic suppression of tumor growth.
With additional laboratory tests, the team found that PHLPP
stops tumor growth by deleting a specific phosphate molecule
at a position called Ser473 on Akt.
The scientists noted
that PHLPP’s role as a tumor suppressor would apply to
all cancers where Akt is elevated, “which is a large number
of cancers,” Newton said.
In addition to Newton,
authors of the paper were first author Tianyan Gao, Ph.D., a
research scientist in the UCSD Department of Pharmacology, and
Frank Furnari, Ph.D., assistant professor, Ludwig Institute
for Cancer Research, UCSD.
The study was funded
by the National Institutes of Health.
first group to demonstrate the biological function of PTEN in
1998 at the University of Michigan was the lab of Jack Dixon,
Ph.D., who is currently UCSD dean for scientific affairs and
professor of pharmacology, cellular & molecular medicine,
and chemistry & biochemistry. His team showed that PTEN
deletes a phosphate molecule from a lipid called phosphatidylinositol
3,4,5-triphosphate (PIP3), which activates Akt.
Sue Pondrom (619) 543-6163