Navigation Links
Gene responsible for hereditary cancer syndrome found to disrupt critical growth-regulating pathway

CAMBRIDGE, Mass. (November 4, 2013) Whitehead Institute scientists report that the gene mutated in the rare hereditary disorder known as Birt-Hogg-Dub cancer syndrome also prevents activation of mTORC1, a critical nutrient-sensing and growth-regulating cellular pathway.

This is an unexpected finding, as some cancers keep this pathway turned on to fuel their unchecked growth and expansion. In the case of Birt-Hogg-Dub syndrome, the mutated gene prevents mTORC1 pathway activation early in the formation of tumors. Reconciling these opposing roles may give scientists a new perspective on how cancer cells can distort normal cellular functions to maintain their own harmful ways.

Cells use the mTORC1 (for "mechanistic target of rapamycin complex 1") pathway to regulate growth in response to the availability of certain nutrients, including amino acids. Whitehead Member David Sabatini and other researchers have teased apart many components of this pathway, but the precise mechanism by which nutrient levels are actually sensed has remained elusive. Recently, Sabatini and his lab determined that a family of proteins known as Rag GTPases act as a switch for the pathwaywhen nutrients are present, the Rag proteins turn on the mTORC1 pathway.

Now, several members of the Sabatini lab, including graduate student Zhi-Yang Tsun, have determined that the FLCN protein acts as a trigger to activate the Rag protein switch. Their work is described in the November 7 issue of the journal Molecular Cell.

"Zhi has ascribed a molecular function to this protein, and that's a major contribution," says Sabatini, who is also a Howard Hughes Medical Institute investigator and a professor of biology at MIT. "For the first time, we have a biochemical function that's associated with it. And in my view, that's an important first step to understanding how it might be involved in cancer."

Before Tsun's work, very little was known about FLCN's role in the cell. In the early 2000s, scientists determined that mutations in the gene coding for FLCN caused the rare cancer Birt-Hogg-Dub syndrome, but the syndrome's symptoms offered little insight into FLCN's molecular function.

Birt-Hogg-Dub syndrome causes unsightly but benign hair follicle tumors on the face, benign tumors in the lungs that can lead to collapsed lungs, and kidney cancer. The syndrome is an autosomal dominant disorder, which means that a child inheriting one mutated copy of the FLCN gene will eventually develop the syndrome. Currently, the disease is managed by treating symptoms, but no cure exists.

FLCN's dual rolesas a cause of a rare cancer in its mutated form and as a trigger for a growth pathway that is often hijacked in cancer cellshas prompted Tsun and Sabatini to rethink how a mutation can push cells to become cancerous.

"Basically, the mTORC1 pathway is essential for life," explains Tsun. "So when you lose this nutrient switch or if it can't be turned on, then the cell seems to freak out and cause all other growth promoting pathways to be turned on to somehow overcompensate for this loss. And this is actually what we see in patient tumors."

For Birt-Hogg-Dub syndrome patients and their families, better understanding of FCLN's function moves the field one step closer to developing a therapy.

"Usually diseases are first described, then the responsible gene or genes are identified, and then that gene's molecular function is figured out," says Tsun. "And you need to know the gene's function before you can start working on drugs or therapy. We've done that third step, which is a very important discovery for these patients."


Contact: Nicole Rura
Whitehead Institute for Biomedical Research

Related biology news :

1. Fertilizer use responsible for increase in nitrous oxide in atmosphere
2. Sports and energy drinks responsible for irreversible damage to teeth
3. New research finds increased growth responsible for color changes in coral reefs
4. A deeper look into the pathogen responsible for crown gall disease in plants
5. Scientists discover new type of virus responsible for a devastating disease in snakes
6. Research identifies mechanism responsible for eye movement disorder
7. Fungus responsible for 5 deaths in the wake of massive tornado
8. Scientists sequence genome of pathogen responsible for pneumocystis pneumonia
9. First in the world - Singapore scientists discover genes responsible for cornea blindness
10. Mutant gene responsible for pigeons head crests
11. No clear evidence more gluten in new wheat is responsible for increase in celiac disease
Post Your Comments:
(Date:11/19/2015)... , Nov. 19, 2015  Based on its ... & Sullivan recognizes BIO-key with the 2015 Global Frost ... year, Frost & Sullivan presents this award to the ... catering to the needs of the market it serves. ... line meets and expands on customer base demands, the ...
(Date:11/18/2015)... 2015  As new scientific discoveries deepen our understanding ... healthcare providers face challenges in better using that knowledge ... addition, as more children continue to survive pediatric cancer, ... old age. John M. Maris, M.D ., ... Philadelphia (CHOP) . --> John M. ...
(Date:11/17/2015)... Paris from 17 th until ... from 17 th until 19 th November ... has invented the first combined scanner in the world which scans ... Until now two different scanners were required: one for passports ... on the same surface. This innovation is an ideal solution ...
Breaking Biology News(10 mins):
(Date:11/30/2015)... , December 1, 2015 Partnership includes an ... for the u niversity , ... support treatment s cale - up ... (ARVs)   Africa , where licensees based anywhere in the ... on SDN technology. --> Africa , where licensees based anywhere ...
(Date:11/30/2015)... Mass. , Nov. 30, 2015 ... HART ), a biotechnology company developing bioengineered organ ... received written notification from The NASDAQ Stock Market ... bid price requirements. The letter noted that as ... HART,s common stock having exceeded $1.00 per share ...
(Date:11/30/2015)... BETHESDA, Md. , Nov. 30, 2015 /PRNewswire/ ... property development company committed to the fostering and ... on the current and prospective initiatives designed to ... , Chief Executive Officer of Spherix. "Based on ... potential future licensees exceeds $50 billion and Spherix ...
(Date:11/30/2015)... 30, 2015  Champions Oncology, Inc. (CSBR), engaged in ... personalize the development and use of oncology drugs, today ... will be presenting at the LD MICRO Investor Conference ... Time (PST).  The conference, held at the Luxe Sunset ... , will feature 200 small/micro-cap companies and is ...
Breaking Biology Technology: