Navigation Links
Oncoproteins double-team and destroy vital tumor-suppressor
Date:2/14/2008

HOUSTON - Two previously unconnected cancer-promoting proteins team up to ambush a critical tumor suppressor by evicting it from the cell's nucleus and then marking it for death by a protein-shredding mechanism, a team led by scientists at The University of Texas M. D. Anderson Cancer Center reports in the Feb. 10 issue of Nature Cell Biology.

The paper is the first to illuminate a mechanism of attack on FOXO3a, a member of the forkhead family of tumor-suppressing proteins, notes senior author Mien-Chie Hung, Ph.D., chair of M. D. Anderson's Department of Molecular and Cellular Oncology.

"We know that FOXO3a is inactivated in about 80 percent of breast tumors, and that it's likely to be inactivated in other solid tumors because three major oncogenic pathways separately target it," Hung said. "The implication is that forkhead activation will be a great therapeutic target because it would be a powerful tumor-suppressor."

Hung and colleagues focused on the effect of the RAS-ERK signaling pathway, which is known to promote tumor growth and proliferation. FOXO3a and its other forkhead cousins have a specific structure - the forkhead box - that allows them to connect with DNA. They are transcription factors, activating or repressing target genes involved in tumor suppression and DNA damage repair.

The team shows in a series of lab experiments that ERK attaches phosphate groups to three specific sites on FOXO3a. This phosphorylated version of FOXO3a is hijacked out of the nucleus, so it can no longer do its job transcribing tumor-suppressing-genes.

Enter the second oncogenic protein, MDM2. MDM2, the team shows, only recognizes the phosphorylated version of FOXO3a. By attaching a string of targeting proteins known as ubiquitins to the phosphorylated tumor suppressor, MDM2 marks it for destruction by the ubiquitin-proteasome degradation pathway.

"Both ERK and MDM2 are well-known oncoproteins, but their collaboration was previously unknown," Hung said.

In a sample of 125 breast cancer tumors, the researchers found that high MDM2 expression and low FOXO3a expression are associated with higher grade tumors.

Additional experiments showed that breast cancer cells treated with healthy FOXO3a and injected into mice resulted in barely measurable tumor volumes after 56 days. Mice injected with cells featuring a disabled version of the tumor-suppressor had an average volume of more than 600 cubic millimeters.

ERK, AKT and IKK are three separate cancer-causing kinases - proteins that phosphorylate other proteins - that Hung calls the Three Musketeers of cancer. All three target FOXO3a. "At least one of these pathways is active in at least 80 percent of solid tumor cancers," Hung says. "ERK alone accounts for 30 percent of human cancers."

"Pharmaceutical companies work to target ERK, AKT and IKK separately," Hung notes. "But activating their forkhead target would work against all three of them. Enhancing FOXO3a could be an effective therapeutic strategy."


'/>"/>

Contact: Scott Merville
sdmervil@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

Related medicine news :

1. Radio waves fire up nanotubes embedded in tumors, destroying liver cancer
2. Researchers train the immune system to deliver virus that destroys cancer in lab models
3. Large intensive care study reveals vital recommendations for treatment of brain injury patients
4. Study details regulation of vital tumor suppressor gene p53
5. Catholic Charities USA Calls on Congress and the President to Protect the Health of Children; Urges President Not to Veto Vitally Important Bill
6. Shop n Save Pharmacy Helps Vitalize Members of Wellness-based Health Insurance Plan
7. Grand Opening of Regence Boys & Girls Club Marks a Milestone in Historic New Columbia Community Revitalization
8. Vital Work of Emergency Nurses Honored Across the Nation During Emergency Nurses Week, October 7-13, 2007
9. VitalKey Introduces the Pink Key(R)
10. DaVita Emergency Response Efforts Ensure Vital Treatment for More than 700 Kidney Failure Patients in Need of Life-Saving Dialysis Treatments in Areas Affected by Southern California Wildfires
11. NIH doubles support for vital HIV/AIDS research center
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:1/20/2017)... ... 20, 2017 , ... Bionic Sports Nutrition LLC, an American company devoted to ... a successful January ECRM Trade Show in Hilton Head, SC. , Bionic Sports ... to provide its products to all clients at reasonable prices. At the ECRM trade ...
(Date:1/20/2017)... ... January 20, 2017 , ... ATP Science, an ... lives, recently attended the January ECRM Trade Show in Hilton Head, SC, benefiting ... its large range of supplements that keep the body functioning at its peak ...
(Date:1/20/2017)... ... January 20, 2017 , ... Michael and Betsy Brauser celebrated 5 years ... Betsy, the clinical trial has been life-saving as she has been on the ... Betsy Brauser was diagnosed with ovarian cancer in 2009. She underwent standard chemotherapy but ...
(Date:1/20/2017)... ... January 20, 2017 , ... ... its sugar-free alternative VW+ 002. The drinks have been produced in collaboration with ... to perform during your workout. , After a successful launch in Sweden last ...
(Date:1/20/2017)... ... January 20, 2017 , ... “The Angel”: a heartwarming and ... out for each of his children. “The Angel” is the creation of published author, ... New York City, and impassioned writer. , When asked of her new book, Marjorie ...
Breaking Medicine News(10 mins):
(Date:1/19/2017)... Jan. 19, 2017 The U.S. Food and Drug ... Idiopathic Constipation (CIC) in adult patients. "No ... disorders," said Julie Beitz , M.D., director of the ... Drug Evaluation and Research. "With the availability of new therapies, ... for their condition." ...
(Date:1/19/2017)... 2017 Many patients don,t realize that they ... a pharmacy just a few blocks away charges only ... problem Medicationdiscountcard.com has created a price comparison ... much their medication will cost at most nearby pharmacies. ... Medicationdiscountcard.com takes all of the ...
(Date:1/19/2017)... , Jan. 19, 2017 Accuray Incorporated (Nasdaq: ... and TomoTherapy® Systems continue to set the bar for ... highest composite overall user satisfaction rating among radiation treatment ... 2016 MD Buyline Market Intelligence Briefing™. The most recent ... composite ratings among industry peers for 11 of the ...
Breaking Medicine Technology: