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Oncoproteins double-team and destroy vital tumor-suppressor
February 15, 2008M. D. Anderson research points to forkhead protein's importance in many types of cancer
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 IKKß 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 IKKß separately," Hung notes. "But activating their forkhead target would work against all three of them. Enhancing FOXO3a could be an effective therapeutic strategy."
University of Texas M. D. Anderson Cancer Center
"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 IKKß 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 IKKß separately," Hung notes. "But activating their forkhead target would work against all three of them. Enhancing FOXO3a could be an effective therapeutic strategy."
University of Texas M. D. Anderson Cancer Center
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Discovery in worms by Queen's researchers points to more targeted cancer treatment
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KEAP1 Keeps major cancer-promoting protein at bay
A tumor-suppressing protein snatches up an important cancer-promoting enzyme and tags it with molecules that condemn it to destruction, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports this week in the journal Molecular Cell.
Genes signal late-stage laryngeal cancer, poorer outcome
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Natural compounds, chemotherapeutic drugs may become partners in cancer therapy
Research in the Linus Pauling Institute at Oregon State University suggests that some natural food compounds, which previously have been studied for their ability to prevent cancer, may be able to play a more significant role in treating it - working side-by-side with the conventional drugs that are now used in chemotherapy.
Tumor suppressor pulls double shift as reprogramming watchdog
A collaborative study by researchers at the Salk Institute for Biological Studies uncovered that the tumor suppressor p53, which made its name as "guardian of the genome", not only stops cells that could become cancerous in their tracks but also controls somatic cell reprogramming.
Researchers uncover potential mechanisms to protect against genetic alterations, diseases
Peering into the DNA of tiny yeast, researchers at the Moores Cancer Center at the University of California, San Diego and the San Diego Branch of the Ludwig Institute for Cancer Research have pinpointed a large number of genes that can prevent a type of genetic rearrangement that may lead to cancer and other diseases.
Tumor mutations can predict chemo success
New work by MIT cancer biologists shows that the interplay between two key genes that are often defective in tumors determines how cancer cells respond to chemotherapy.
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Tumor Suppressor Genes by Katherine R. Polinsky (Editor) A tumour suppressor gene is a gene that reduces the probability that a cell in a multicellular organism will turn into a tumor cell. A mutation or deletion of such a gene will increase the probability of the formation of a tumor. Unlike oncogenes, tumor suppressor genes generally follow the 'two-hit hypothesis', which implies that both alleles that code for a particular gene must be affected before an effect is manifested. This is due to the fact that if only one allele for the gene is damaged, the second can still produce the correct protein. However, there are cases where mutations in only one allele will cause an effect. A notable example is the gene that codes for p53. Tumor suppressor genes, or more precisely, the proteins for which they code, either have a dampening or repressive... |
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Tumor Suppressor Genes: An entry from Macmillan Reference USA's Macmillan Reference USA Science Library: Genetics by Giles Watts (Author) This digital document is an article from Macmillan Reference USA Science Library: Genetics, brought to you by Gale®, a part of Cengage Learning, a world leader in e-research and educational publishing for libraries, schools and businesses. The length of the article is 1047 words. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. A comprehensive collection of articles on all aspects of genetics, from Mendel to the decoding of the human genome. Explains the workings of genes and chromosomes, genetic diseases, and biotechnology. Covers the ethical, legal, and social issues connected to genetic science and includes coverage of careers in the field. | |
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Tumor suppressor gene inactivation during cadmium-induced malignant transformation of human prostate cells correlates with overexpression of de novo DNA ... from: Environmental Health Perspectives by Lamia Benbrahim-Tallaa (Author), Robert A. Waterland (Author), Anna L. Dill (Author), Mukta M. Webber (Author), Michael P. Waalkes (Author) This digital document is an article from Environmental Health Perspectives, published by Thomson Gale on October 1, 2007. The length of the article is 4339 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Tumor suppressor gene inactivation during cadmium-induced malignant transformation of human prostate cells correlates with overexpression of de novo DNA methyltransferase.(Research)(deoxyribonucleic acid)(Clinical report) Author: Lamia Benbrahim-Tallaa Publication: Environmental Health Perspectives (Magazine/Journal) Date: October 1, 2007 Publisher: Thomson... | |
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