|NCI Scientists Identify Novel Protein That Ties
Disruption of a Critical Cellular Pathway to Birt-Hogg-Dubé Syndrome
Researchers at the National Cancer Institute (NCI), part of the
National Institutes of Health, have linked specific genetic mutations
to defects in cells that lead to a rare disease known as Birt-Hogg-Dubé syndrome.
Building on previous clinical and genetic work spanning several
years, the researchers discovered a novel protein that binds to
the normal version, but not the mutant version, of the protein
implicated in Birt-Hogg-Dubé syndrome. This new protein, which
they named folliculin interacting protein 1 (or FNIP1), links Birt-Hogg-Dubé syndrome
to disruptions in critical energy- and nutrient-sensing cellular
pathways. The findings appear online October 2, 2006, in The
Proceedings of the National Academy of Sciences. The research
was led by Masaya Baba, M.D., Ph.D., and a team of scientists from
NCI’s Center for Cancer Research*.
“These findings open new avenues of further research and therapeutic
development for Birt-Hogg-Dubé syndrome, as well as other diseases
and cancers related to the same pathways,” said NCI Director John
Niederhuber, M.D. “Although Birt-Hogg-Dubé syndrome is relatively
rare, it is an important disease to study not only for the sake
of these patients, but also for the further understanding we will
gain about the basic cellular defects of both Birt-Hogg-Dubé and
Birt-Hogg-Dubé syndrome, first described in 1977 by its namesake
physicians, is characterized by benign tumors of hair follicles,
lung cysts and, in some cases, the development of kidney cancer.
In 2001, researchers in the Urologic Oncology Branch of NCI’s Center
for Cancer Research, working in partnership with Birt-Hogg-Dubé patients
and their families, mapped the genetic location of the responsible
gene to chromosome 17. In 2002, they discovered multiple mutations
in a novel, previously unidentified gene on chromosome 17, which
they named “BHD.” Folliculin, or FLCN, is the protein
product of the BHD gene.
According to Laura S. Schmidt, Ph.D., corresponding author of
the Proceedings paper and staff scientist at the Urologic
Oncology Branch of NCI’s Center for Cancer Research, “Focusing
on how alterations in protein interactions actually result in disease
symptoms is critical to the development of truly effective therapies.”
Recent findings from other studies of noncancerous growths, including
birthmarks, suggest that mutations in genes that code for proteins
that are involved in critical energy/nutrient-sensing molecular
pathways underlie the pathologic conditions seen in these diseases.
These molecular pathways converge on the protein product of a key
regulatory gene known as mammalian target of rapamycin (mTOR),
leading researchers to question whether FCLN was an element in
an mTOR-related pathway. To accomplish this, they first sought
to identify the proteins that interact with FCLN in normal living
By isolating groups of interacting proteins, they found that one
protein in particular, FNIP1, tightly binds to FLCN. They also
determined that the binding of FNIP1 to FLCN in normal cells occurs
in the section of the protein that is missing in mutated forms
of FLCN identified in Birt-Hogg-Dubé patients.
The results of these studies give new direction to understanding
not only Birt-Hogg-Dubé syndrome, but also additional diseases
and cancers that are linked to defects in mTOR and other pathways.
In addition, previous work suggests that FLCN acts as a tumor suppressor,
although the mechanism for that activity is still being studied.
“I am encouraged by our progress in understanding how these genes
contribute to cancer, and I am hopeful that this type of work will
lead more quickly to effective forms of treatment,” said W. Marston
Linehan, M.D., chief of the NCI’s Urologic Oncology Branch and
an author of the Proceedings paper. “The support of NCI
for this kind of long-term, focused study is absolutely necessary
as we seek to understand and treat the many different cellular
mechanisms that can contribute to the formation of cancer.”
* Baba M, Hong S, Warren MB, Sharma N, Nickerson
ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF, Hartley JL,
Furihata M, Oishi S, Zhen W, Burke TR, Linehan WM, Schmidt LS and
Zbar B. Folliculin encoded by the BHD gene interacts with
a novel binding protein, FNIP1, and AMPK, and is involved in AMPK
and mTOR signaling. PNAS, online edition, October 2, 2006.
For more information on other research in Dr. Linehan’s lab, please
go to http://ccr.cancer.gov/staff/staff.asp?profileid=5755.
For more information about Dr. Schmidt’s lab, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=9565.
For more information about cancer, visit the NCI Web site at http://www.cancer.gov or
call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
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Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.