'Shuttling' Protein Possibly Key To Resilience Of Cancer Cells

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'Shuttling' Protein Possibly Key To Resilience Of Cancer Cells

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Alzheimer's Cardiovascular/Cardiology

Main Category: Cancer/Oncology News

Article Date: 10 Mar 2006 - 20:00pm (UK)

WEST LAFAYETTE, Ind. - Researchers at Purdue University have

discovered a molecular mechanism that may play a crucial role in

cancer's ability to resist chemotherapy and radiation treatment and

that also may be involved in Alzheimer's and heart disease.

The scientists, using an innovative imaging technique invented at

Purdue, have learned that a protein previously believed to be

confined to the nucleus of healthy cells actually shuttles between

the nucleus and cytoplasm, the region of the cell surrounding the

nucleus. Moreover, the protein's shuttling is controlled by the

presence of another protein in the nucleus and its attachment to that

second protein.

" Our findings may provide a new avenue for the development of

innovative treatments for certain cancers and other conditions, " said

Chang-Deng Hu, an assistant professor in Purdue's Department of

Medicinal Chemistry and Molecular Pharmacology and an investigator at

the Walther Cancer Institute in Indianapolis.

The experiments were done using a line of " teratocarcinoma " malignant

tumor cells from mice called F9, which, when subjected to the right

biochemical signals, have the ability to alter their properties and

are considered to be " cancer stem cells. " The hypothetical cancer-

resistance role of cancer stem cells could explain why tumors return

after treatment. If stem cells prove to be critical to cancer's

resistance to treatment, new medications might be developed to target

cancer stem cells while chemotherapy or radiation is administered, Hu

said.

Research findings are detailed in a paper appearing this month in the

EMBO Journal, published by the European Molecular Biology

Organization. The paper was written by postdoctoral research

associate Han Liu, laboratory technician Xuehong Deng and graduate

student Y. Shyu, all in the Department of Medicinal Chemistry

and Molecular Pharmacology; Jian Jian Li, an associate professor in

the Department of Health Sciences; J. Taparowsky, a

professor in the Department of Biological Sciences; and Hu.

The research focuses on two proteins called c-Jun and ATF2, which are

key components of a protein complex called activating protein-1, or

AP-1. AP-1 is a major " transcription factor " that binds to DNA,

activating the " expression " of genes required to produce proteins

needed for vital cellular processes. The proteins that make up AP-1,

including ATF2 and c-Jun, often join together in the nucleus, forming

either " homodimers, " when two of the same proteins join,

or " heterodimers, " when two different proteins come together.

" Current thinking is that all of these AP-1 proteins in healthy cells

are localized, or confined, to the nucleus, " Hu said. " But in this

work we found for the first time that ATF2 constantly shuttles

between the cytoplasm and the nucleus. "

The researchers found that the ATF2 protein possesses " nuclear

export " and " nuclear localization " signals, which enable it to travel

out of and back into the nucleus, respectively. The researchers also

discovered that if ATF2 attaches to c-Jun in the nucleus, forming a

heterodimer, the nuclear export signal is blocked, preventing ATF2

from traveling from the nucleus to the cytoplasm.

Researchers had already known that chemotherapy and radiation cause

cancer cells to increase production of ATF2. The Purdue researchers

found that " overexpressed, " or overproduced, ATF2 is predominantly

located in the cytoplasm because of an inadequate amount of c-Jun in

the nucleus, suggesting it is likely that overexpressed ATF2 also may

be localized in the cytoplasm in cancer cells, Hu said.

The Purdue researchers not only discovered that ATF2 is localized in

the cytoplasm of the mouse cancer stem cells, but also that exposing

the cells to ultraviolet light induced more production of c-Jun

protein in the nucleus, causing the ATF2 to bind with c-Jun, stopping

the shuttling process and causing cell death. The c-Jun-ATF2

heterodimers cause more c-Jun protein to be produced, attracting more

ATF2 and reinforcing the localization of ATF2 in the nucleus.

Because it has been reported that ATF2 overexpression causes the

resistance of cancer cells to chemotherapy and radiation, the ATF2

shuttling might play a key role in the ability of cancer cells to

resist cancer treatments, and preventing the ATF2 from moving into

the cytoplasm might improve the effectiveness of anticancer

treatments.

" Ultimately, we are trying to figure out how to make the cancer cells

more sensitive to chemotherapy and radiation treatment by keeping the

ATF2 in the nucleus, " Hu said.

The Purdue researchers tracked ATF2 and other proteins using a

fluorescent imaging technique developed by Hu called bimolecular

fluorescence complementation. The procedure involves breaking a

fluorescent protein into two fragments and then fusing each fragment

to different AP-1 proteins, including c-Jun and ATF2. When the

proteins later bind to form a heterodimer, the fluorescent-protein

fragments are reunited, causing them to glow green when illuminated

with a light source. The fluorescence enabled the researchers to

pinpoint the location of c-Jun-ATF2 heterodimers and discover the

shuttling movements of ATF2. The ATF2 protein also has been found in

the cytoplasm of diseased brain cells in Alzheimer's disease and

muscle cells in the heart, suggesting the same shuttling mechanism

might be involved in those conditions.

" These findings suggest a new avenue to study how ATF2 is implicated

in the pathogenesis of these diseases, " Hu said.

###

Hu and co-authors Li and Taparowsky are affiliated with the National

Cancer Institute-designated Purdue Cancer Center and with the

Oncological Sciences Center in Discovery Park, the university's hub

for interdisciplinary research. The research has been funded by the

Purdue Cancer Center, Indiana Elks Charities Inc., Walther Cancer

Institute, National Institutes of Health and National Science

Foundation.

Writer: Emil Venere, (765) 494-4709, venere@...

Sources: Chang-Deng Hu, (765) 496-1971, cdhu@...

Jian Jian Li, (765)496-6792, jjli@...

J. Taparowsky, (765)494-7978, ejt@...

Related Web sites:

Chang-Deng Hu: http://www.mcmp.purdue.edu/faculty/hu.php

Jian Jian Li: http://www.healthsciences.purdue.edu/people/faculty.php?

uid=jjli

J. Taparowsky:

http://www.biology.purdue.edu/people/faculty/taparowsky/index.htm

STORY AND PHOTO CAN BE FOUND AT:

http://news.uns.purdue.edu/UNS/html4ever/2006/060307.Hu.shuttling.html

Note to Journalists: The research paper has been posted online at

http://www.nature.com/emboj/journal/vaop/ncurrent/full/7601020a.html.

A publication-quality illustration depicting the shuttling protein is

available at http://news.uns.purdue.edu/UNS/images/+2006/hu-

shuttling.jpg

PHOTO CAPTION:

This diagram depicts how a protein called ATF2 constantly shuttles

from the nucleus to the cytoplasm in cells, a mechanism that may play

a crucial role in cancer's ability to resist chemotherapy and

radiation treatment and that also may be involved in Alzheimer's and

heart disease. ATF2 was previously believed to be confined to the

nucleus of healthy cells, but researchers at Purdue University

discovered that it actually shuttles between the nucleus and

cytoplasm. The researchers used a novel imaging technique invented at

Purdue to track the protein, learning that its shuttling is

controlled by the presence of another protein in the nucleus and its

attachment to that second protein. The findings could provide a new

avenue for the development of innovative treatments for certain

cancers and other conditions. (Purdue Department of Medicinal

Chemistry and Molecular Pharmacology)

A publication-quality photo is available at

http://news.uns.purdue.edu/UNS/images/+2006/hu-shuttling.jpg

Contact: Emil Venere

venere@...

Purdue University