NEW YORK (Reuters Health) - The Pokemon (POK erythroid myeloid ontogenic factor) gene leads to overt oncogenic transformation in many human cancers by repressing transcription of the tumor suppressor gene ARF, investigators report in the January 20th issue of Nature.
Their research findings “provide a further rational for transcription-based therapeutic modalities and identify Pokemon as an important target for therapy on the basis of its key role in oncogenesis,” senior author Dr. Pier Paolo Pandolfi, at Memorial Sloan-Kettering Cancer Center, New York, and his associates propose.
“Pokemon is known to be partner in crime with another oncogene, BCL6, involved in lymphoma pathogenesis,” Dr. Pandolfi told Reuters Health. “The initial reason to study Pokemon was to ask if it is cooperating with BCL6 or antagonizing BCL6. When we started playing with Pokemon we discovered it is an oncogene itself, that can in fact transform cells.”
Dr. Pandolfi’s group first showed that in mouse embryonic fibroblast cells -- where combinations of potent oncogenes normally elicit a strong proliferative response -- blocking expression of Pokemon prevented cellular transformation, although the cells continued to proliferate normally.
In contrast, Pokemon co-expression blocked oncogene-induced apoptosis and senescence. They found that it did so by preventing expression of ARF.
“In other words,” Dr. Pandolfi said, “Pokemon is sitting at the very bottom end of this transformation process and acting as a main switch.”
“As far as we know, this is the first oncogene found to be essential for other oncogenes to act,” he added.
Mice engineered to overexpress Pokemon exhibited aggressive tumors, with thymic enlargement, lymphadenopathy, splenomegaly, hepatomegaly and tumor infiltration into bone marrow.
The researchers also found Pokemon to be strongly expressed in some human T- and B-cell lymphomas. Paradoxically, Pokemon positivity was associated with better overall survival. This fits the paradigm in which more actively proliferating cells are more responsive to chemotherapy and radiation therapy, Dr. Pandolfi explained.
Further research has shown that Pokemon is widely expressed in other solid human tumors, the he added, which bodes well for the efficacy of new therapies developed to target Pokemon expression.
Source: Nature 2005;433:278-285. [ Google search on this article ]
MeSH Headings:Biological Phenomena, Cell Phenomena, and Immunity: Cell Physiology: Cell Transformation, Neoplastic: Neoplastic Processes: Biological SciencesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
