Role of the proto-oncogene Pokemon in cellular transformation and ARF repression

Abstract

Aberrant transcriptional repression through chromatin remodelling and histone deacetylation has been postulated to represent a driving force underlying tumorigenesis because histone deacetylase inhibitors have been found to be effective in cancer treatment. However, the molecular mechanisms by which transcriptional derepression would be linked to tumour suppression are poorly understood. Here we identify the transcriptional repressor Pokemon (encoded by the Zbtb7 gene) as a critical factor in oncogenesis. Mouse embryonic fibroblasts lacking Zbtb7 are completely refractory to oncogene-mediated cellular transformation. Conversely, Pokemon overexpression leads to overt oncogenic transformation both in vitro and in vivo in transgenic mice. Pokemon can specifically repress the transcription of the tumour suppressor gene ARF through direct binding. We find that Pokemon is aberrantly overexpressed in human cancers and that its expression levels predict biological behaviour and clinical outcome. Pokemon's critical role in cellular transformation makes it an attractive target for therapeutic intervention.

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Figure 1: Pokemon is indispensable for cellular transformation and acts as a proto-oncogene.
Figure 2: Pokemon is a key ARF transcriptional repressor.
Figure 3: p19Arf loss reverts premature senescence and refractoriness to oncogenic transformation in Zbtb7-/- MEFs.
Figure 4: Pokemon transgenic mice develop pre-T LBL.
Figure 5: Cooperative roles of Pokemon and BCL6 in lymphomagenesis.

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Acknowledgements

We thank D. Yao, C. Hedvat, M. Dudas, J. Qin and A. Wilton for assistance on TMA preparation, staining and statistical analyses; S. Hasan for assistance with data input and management; K. Manova, C. Farrell and other Molecular Cytology Core Facility members for advice and assistance with IHC; J. Overholser and other Monoclonal Antibody Core Facility staff for help with antibody generation; G. Cattoretti and R. Dalla-Favera for advice; and L. Khandker, L. Dong, M. Hu, L. DiSantis and other P.P.P. laboratory members for assistance and discussion. This work is supported in part by an NCI grant to P.P.P.

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Correspondence to Pier Paolo Pandolfi.

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Supplementary information

Supplementary Figure S1

The protein expression levels of introduced oncogenes. (JPG 25 kb)

Supplementary Figure S2

Identification of Pokemon binding sequence. (JPG 65 kb)

Supplementary Figure S3

Schematic representations of the ARF promoter. (JPG 97 kb)

Supplementary Figure S4

The expression levels of Pokemon mRNA in transgenic founder lines. (JPG 29 kb)

Supplementary Figure S4

POKEMON expression in human and mouse normal lymphoid tissues. (JPG 86 kb)

Supplementary Figure S6

Kaplan-Meier curves for various prognostic markers. (JPG 75 kb)

Supplementary Tables S1 and S2

Clinical and immunohistochemical characteristics of DLBCL patients (Supplementary Table S1), and Clinical and immunohistochemical characteristics of FL patients (Supplementary Table S2). (DOC 44 kb)

Supplementary Figure Legends

Legends to accompany the above Supplementary Figures. (DOC 58 kb)

Supplementary Methods

Contains details of additional methods (retrovirus infection; real-time PCR analysis; ChIP assay; pokemon mRNA expression level in transgenic founder lines; flow cytometry analysis; immunohistochemistry for paraffin-embedded tissues; and the statistical analysis) used in this study, and an additional reference. (DOC 42 kb)

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Maeda, T., Hobbs, R., Merghoub, T. et al. Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature 433, 278–285 (2005). https://doi.org/10.1038/nature03203

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