Re: From Marie

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WOW!!!

>

> Public release date: 1-May-2003

>

>

> Contact: McGreevey

> smcgreevey@p...

>

> Massachusetts General Hospital

>

> Researchers identify important function of NF2 tumor suppressor

> Protein plays role in inherited cancer syndrome, may be key to

other tumors

> A research team based at Massachusetts General Hospital (MGH) has

identified

> a key cellular function of a protein known to be involved in the

rare

> genetic disorder neurofibromatosis type 2 (NF2). The protein,

called merlin,

> plays a key role in cell-to-cell communication and may be involved

in other

> types of cancer. The discovery also may support the theory that

some tumors

> are destined to spread or metastasize from the outset, rather than

gaining

> the ability to spread as they develop. The report appears in the

May 1, 2003

> issue of Genes & Development.

> NF2 is a rare inherited disorder characterized by multiple tumors

of the

> spine and brain. The NF2 gene was discovered in 1993 by

researchers from MGH

> and elsewhere. At the time of its discovery it was apparent that

the NF2

> gene was a tumor suppressor, but its exact function was unclear.

The protein

> encoded by the NF2 gene, given the name merlin, was found at the

interface

> of the cell membrane with the cytoskeleton, a network of filaments

that

> supports the cell.

> " Since merlin is a tumor suppressor whose loss of function leads

to tumor

> development, it is absolutely critical to define what happens when

this

> function is lost, " says McClatchey, PhD, of the MGH Cancer

Center,

> the senior author of the current report. " Our objective was to

define the

> primary cellular and molecular consequences of that loss of

function. "

> McClatchey and her colleagues had previously developed a strain of

mice

> genetically engineered to lack normal Nf2 genes. This animal model

allowed

> them to identify the gene's function by comparing cells from the

Nf2-mutant

> mice with cells of the same type from normal mice. They found

that, while

> the Nf2-deficient cells looked normal and multiplied normally,

they did not

> stop multiplying when they came into contact with other cells in

the culture

> dish. The normal cells stopped growing when they filled the

culture dish,

> but the Nf2-deficient cells kept piling up on each other,

suggesting that

> the cells could not sense they were touching other cells.

> Followup experiments showed that the Nf2-deficient cells were

lacking key

> cellular structures called adherens junctions. Located in the cell

membrane,

> adherens junctions connect adjacent cells and are known to play a

role in

> cell-to-cell communications. The researchers found merlin in the

adherens

> junctions of normal cells and discovered that adding normal merlin

protein

> to cultures of Nf2-deficient cells restored both the formation of

adherens

> junctions and contact-dependent growth inhibition.

> " Our study suggests that, through its link to the cellular

cytoskeleton,

> merlin normally organizes the structure that facilitates cell-to-

cell

> communication – the adherens junction, " says McClatchey, who is an

assistant

> professor of Pathology at Harvard Medical School. " Loss of junction

> integrity has been linked to both tumor development and tumor

invasion,

> providing an explanation for the striking development of

metastatic cancer

> in Nf2-mutant mice, "

> McClatchey notes that NF2 mutations in humans have also been

associated with

> mesothelioma, a highly malignant type of lung cancer caused by

asbestos

> exposure, and may be associated with other forms of cancer. She

believes

> that future research may show that NF2 mutations induced by

environmental or

> other factors could play a broader role in cancer development and

that

> strategies to restore or enhance merlin function may lead to

potential

> therapies for NF2-associated cancer.

> The current finding also echoes other recent studies that may

change some

> fundamental theories about cancer development. It has been thought

that as

> tumors develop and cells keep mutating, some of them acquire

characteristics

> that enable them to spread beyond the original site, essentially

to become

> malignant. However, some recent studies that examine which genes

are

> expressed or turned on in tumor cells suggest that the capacity to

> metastasize is inherent from the original tumor-inducing mutation.

> " Given that loss of adherens junctions has been linked to both

tumor

> initiation and tumor metastasis, " says McClatchey, " loss of NF2

may be an

> example of an event that both starts a tumor and confers metastatic

> potential. "

> ###

> McClatchey's co-authors are first author Dominique Lallemand, PhD,

Marcello

> Curto, MD, PhD, and Ichiko Saotome all of the MGH Cancer Center;

and Marco

> Giovannini, MD, PhD, of INSERM (French National Institute for

Health and

> Medical Research) in Paris. The research was supported by grants

from the

> Amerian Cancer Society, the Department of Defense

Neurofibromatosis Program,

> Ligue Contre le Cancer (France), the National Neurofibromatosis

Foundation,

> and the Association pour la Recherche Contre le Cancer (French

Association

> for Cancer Research).

> Massachusetts General Hospital, established in 1811, is the

original and

> largest teaching hospital of Harvard Medical School. The MGH

conducts the

> largest hospital-based research program in the United States, with

an annual

> research budget of more than $350 million and major research

centers in AIDS

> cardiovascular research, cancer, cutaneous biology,

neurodegenerative

> disorders, transplantation biology and photomedicine. In 1994, MGH

and BWH

> joined to form Partners HealthCare System, an integrated health

care

> delivery system comprising the two academic medical centers,

specialty and

> community hospitals, a network of physician groups and nonacute

and home

> health services.

>

>

>

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