May 04, 2001
Researchers Closer to Understanding Tuberous Sclerosis
Researchers have new evidence that may help explain how two genes
that are mutated in patients with tuberous sclerosis complex, a genetic
disorder that produces widespread benign tumors in the brain, skin,
lungs and kidneys, contribute to regulating cell growth and organ
size.
In an article published in the May 4, 2001, issue of the journal
Cell, Howard Hughes Medical Institute investigator Tian Xu
and colleagues at Yale University School of Medicine report that the
fruit fly protein Tsc1 is responsible for maintaining normal cell size.
The fly protein is homologous to TSC1, which is one of two human
proteins that malfunctions in patients who have tuberous sclerosis
complex.
“In trying to understand tumorigenesis, a great deal of attention has been paid to the proliferation of cells as an underlying cause. But our studies of these regulatory proteins suggest that deregulation of organ size may be another important step in tumorigenesis.”
Tian Xu
Xu and colleagues Christopher J. Potter and He Huang also showed
that Tsc1 and Tsc2 interact with each other and are likely to be part
of the insulin-signaling pathway. The discoveries suggest new molecular
targets for therapies designed to treat tuberous sclerosis complex.
Furthermore, since the proteins are also part of the insulin-signaling
pathway, they may be attractive targets for novel therapies for type 2
diabetes, said Xu.
"Researchers have long known that in humans, mutations in the genes
for either TSC1 or TSC2 cause this dominant inherited disorder," said
Xu. "And, they have known that the two proteins normally bind to one
another in the regulatory process. While it was known that the various
mutant proteins were all truncated and didn’t bind to each other,
there was no clue how that lack of binding caused tuberous sclerosis
and how the disorder could be treated."
Xu and his colleagues began their studies by creating genetic mosaic
flies. The genetic mosaic flies were originally developed as a way to
screen for gene mutations that affect growth. Creating mosaic flies
allows researchers to identify gene mutations that might be missed if
mutations result in early lethality. In generating mosaic flies, the
researchers first use chemicals to induce genetic mutations in the
flies. They next examine the normally well-ordered pattern of cells in
the flies’ eyes for the telltale signs of overgrowth that may
characterize mutations in genes that control cell growth.
"This technique mimics the tumorigenic process in humans, because
like humans, these flies are chimeric—they have only a few
somatic cells that have mutated tumor suppressor genes or oncogenes,"
said Xu.
In screening mosaic flies for mutations, Xu and his colleagues
discovered one mutant that exhibited an abnormal growth of eye cells
that resembled the increase in cell size seen in patients with tuberous
sclerosis complex. In humans and flies, these cells grow to roughly
three times their normal size, which causes an increase in organ size
and tumor development.
In these overgrown eye cells, the scientists found the same type of
mutation in Tsc1 that is found in patients who have tuberous
sclerosis complex. As in humans, the mutation in the fly Tsc1
gene caused larger cell growth, cell proliferation and increased organ
size.
In additional experiments, the researchers also showed that the fly
proteins Tsc1 and Tsc2 bound to each other and worked in concert just
as they do in humans. "While it was important to show that the fly
system was like that of humans, the most critical contribution of this
study was in identifying the metabolic pathway that these proteins
affected," said Xu. The scientists’ previous studies had shown
that mutations in the molecule dPTEN negatively regulates the insulin
signaling pathway – which other researchers had shown to be
critical for regulating cell size, cell number and organ size in
mammals as well.
However, Xu and his colleagues also found that the mutant Tsc1
produced the same overactivation of the insulin pathway, which resulted
in enlarged cells like those seen in the dPTEN mutants.
A number of detailed experimental manipulations of regulatory
proteins in the insulin pathway revealed that the Tsc1 and Tsc2
proteins fit into that pathway—a finding which could have
implications for therapy. In particular, said Xu, their experiments
showed that an enzyme called S6 kinase that is part of the insulin
signaling pathway could be a highly promising drug target for treating
tuberous sclerosis.
"Delineating this pathway has suggested that targeting the S6
kinase, which functions downstream of Tsc1 and Tsc2, may be a potential
novel therapy for tuberous sclerosis," explained Xu. "We previously had
no clue about the affected pathway, and now suddenly we know where to
target drugs for this disorder."
Another byproduct of the work, said Xu, is that it may help patients
with type 2 diabetes. People who have type 2 diabetes usually don't
make enough insulin to metabolize glucose properly. In humans, TSC1 and
TSC2 both negatively regulate insulin signaling, so disrupting their
function may prove to be a useful treatment for type 2 diabetes, said
Xu. "The insulin-signaling pathway is conserved from flies to humans,
so these studies suggest that in patients with type 2 diabetes, the
TSC1 and TSC2 complex might be a target for therapeutic drugs," said
Xu. By using drugs to thwart the binding of the two proteins
selectively, explained Xu, one might be able to activate the insulin
signaling pathway without producing the symptoms of tuberous sclerosis
as a side effect.
Finally, said Xu, finding that mutations in Tsc1 affect organ growth
might have implications for understanding fundamental aspects of tumor
growth. "In trying to understand tumorigenesis, a great deal of
attention has been paid to the proliferation of cells as an underlying
cause," said Xu. "But our studies of these regulatory proteins suggest
that deregulation of organ size may be another important step in
tumorigenesis."
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