NEW YORK, January 20, 2005 - Scientists at Memorial Sloan-Kettering Cancer Center (MSKCC) have identified a new cellular oncogene essential for the development of cancer. Oncogenes are genes that, when mutated or dysfunctional, lead normal cells to become cancerous. The investigators have named the gene POKEMON (for POK Erythroid Myeloid Ontogenic factor). The work is being published in the January 20, 2005, issue of Nature.
"There are a number of genes that can cause cancer, the so-called oncogenes, but Pokemon is unique in that it is needed for other oncogenes to cause cancer." said MSKCC cancer geneticist Pier Paolo Pandolfi, MD, PhD, the senior author of the study. "More important, because the Pokemon protein plays such a crucial role in the formation of cancer, it could prove to be an effective target for new drug therapies."
Pokemon works by controlling the pathways that are required to transform normal cells to cancerous ones. The researchers found that when they "knocked out" the Pokemon gene in mice, that transformation was blocked and cells do not become cancerous. (Knocking out a gene means inactivating it through genetic engineering.) A drug that could block the protein's function in the same way could be a powerful anticancer agent.
"Pokemon is a main switch in the molecular network that leads toward cancer," Dr. Pandolfi added. "If we could turn Pokemon off, it may block this oncogenic circuitry and stall the malignant process."
The investigators confirmed Pokemon's cancer-causing role by inserting the oncogene into mice. Pokemon does its damage by repressing the function of other proteins, including a tumor suppressor called ARF. The mice developed aggressive, fatal forms of lymphoma. In further work, using a technique called tissue micro arrays to study tumor samples from people with many types of cancer, they confirmed that Pokemon is present in very high levels in certain types of B-cell and T-cell lymphomas. They also found that tumors with high levels of Pokemon protein were much more likely to be aggressive.
"Pokemon is a member of a family of proteins that are known to be transcription factors and are mutated in human cancer," said Takahiro Maeda, MD, PhD, a postdoctoral research fellow in Dr. Pandolfi's laboratory who was the paper's first author. "It is likely that the protein plays a role in solid tumors as well, and we now have means to specifically interfere with the activity of these transcription factors."
Other authors on the paper were Robin M. Hobbs, PhD; Taha Merghoub, PhD; Ilhem Guernah, MS; Carlos Cordon-Cardo, MD, PhD; and Julie Teruya-Feldstein, MD from MSKCC; and Arthur Zelent, PhD, of the Institute of Cancer Research in the United Kingdom. The work was supported in part by a grant from the National Cancer Institute.
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