Pokemon Protein Implicated in Cancer Development
A central problem in combating cancer has been its molecular complexity; each cancer cell has numerous mutated genes contributing to the disease. However, a study, funded in part by the National Cancer Institute (NCI), which appears in the January 20 Nature identifies a new cancer gene, named Pokemon, that may act as a master switch. Pokemon is an oncogene, a gene that can cause normal cells to become cancerous when mutated, but its role is unique in that it controls the activity of other oncogenes.
"Pokemon is a main switch in the molecular network that leads toward cancer," said senior author Dr. Pier Paolo Pandolfi of Memorial Sloan-Kettering Cancer Center (MSKCC). "If we could turn Pokemon off, it may block this circuitry and stall the malignant process."
Pokemon (POK Erythroid Myeloid Ontogenic factor) is part of the POK gene family that encodes proteins that turn off other genes. POK proteins are critical in embryonic development, cellular differentiation, and oncogenesis.
Dr. Pandolfi and colleagues at MSKCC, along with collaborators at Chester Beatty Laboratories in London, examined the potential role of this POK member in cancer development. They first introduced multiple combinations of cancer-triggering genes into normal and Pokemon-deficient mouse cells. These stimuli caused normal cells to proliferate rapidly and become cancerous, whereas cells lacking Pokemon did not respond and remained healthy. In addition, co-expressing Pokemon and another oncogene in normal cells increased the proliferation of the cells as compared with expressing the other oncogene alone.
The researchers found that one reason Pokemon had such a broad effect was that it could turn off the expression of the key tumor suppressor p19ARF. The authors note that Pokemon is the first ARF-specific repressor to be identified. "Pokemon is a novel regulator of a critical pathway," noted Dr. Michael Dean, principal investigator in NCI's Laboratory of Genomic Diversity. "The p19 gene is one of the 'big three' tumor suppressors, along with p53 and retinoblastoma protein; at least one of these is mutated or inactivated in virtually every cancer."
The researchers tested Pokemon's effect in mice to examine if it could genuinely act as an oncogene and stimulate cancer development. They generated mouse strains which overexpressed Pokemon, and observed that many of these mice developed aggressive fatal lymphomas.
To see if the results of the mouse models could be related to humans, the researchers used microarrays to look at Pokemon expression in human tumors. About 80 percent of large B-cell and follicular lymphomas analyzed for gene expression displayed at least moderate levels of Pokemon expression, and one-third of the tumors had high expression levels. Although Dr. Dean noted that it may be too soon to generalize Pokemon activity with human cancers, excess Pokemon was also found in subsets of breast, lung, colon, prostate, and bladder tumors.
By Jo-Ann Kriebel