Editors' ChoiceCancer

Too Much Repression Leads to Cancer

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Science's STKE  25 Jan 2005:
Vol. 2005, Issue 268, pp. tw32
DOI: 10.1126/stke.2682005tw32

New evidence points to an important role for the transcriptional repressor known as Pokemon in oncogenesis. Maeda et al. studied the effects of ablation or overexpression of Pokemon. The Pokemon (POK erythroid myeloid ontogenic factor, also called LRF, OCZF, or FBI-1) protein belongs to a family of proteins that contain a POZ domain (poxvirus and zinc finger, also called BTB domain) and a DNA-binding domain, through which they act as transcriptional repressors. Loss of Pokemon in mouse embryo fibroblasts made cells resistant to the effects of potent oncogene combinations. When expressed with various oncogenes, Pokemon enhanced transformation and protected cells from apoptosis or senescence. In vivo Pokemon promoted oncogenesis when overexpressed in T and B cells in a transgenic mouse model. The authors used a technique known as CAST (cyclic amplification and selection of targets) and electrophoretic mobility-shift assays to characterize a Pokemon binding sequence. A search of tumor suppressor genes with potential binding sites turned up ARF, a protein that works with the tumor suppressor p53 as a major defense mechanism against oncogenes. This repression of ARF expression appeared to be critical, as knockout of Arf in mouse embryo fibroblasts protected cells from the transforming effects of loss of Pokemon. Pokemon was overexpressed in certain human cancers, and the amount of Pokemon expression was a predictor of clinical outcome. Thus Pokemon has all the hallmarks of a critical regulator of transformation and oncogenesis and provides a likely target for effective use of transcriptional regulators for therapeutic effects against cancer.

T. Maeda, R. M. Hobbs, T. Merghoub, I. Guernah, A. Zelent, C. Cordon-Cardo, J. Teruya-Feldstein, P. P. Pandolfi, Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature 433, 278-285 (2005). [PubMed]

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