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Role
of the proto-oncogene Pokemon in cellular transformation and ARF
repression
Takahiro Maeda1,2,
Robin M. Hobbs1,2, Taha Merghoub1,2,
Ilhem Guernah1,2, Arthur Zelent3,
Carlos Cordon-Cardo2, Julie Teruya-Feldstein2
& Pier Paolo Pandolfi1,2
1Cancer Biology and Genetics Program, 2Department
of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering
Institute, 1275 York Avenue, New York, New York 10021, USA. 3Leukemia
Research Fund Center at the Institute of Cancer Research, Chester
Beatty Laboratories, Fulham Road, London SW3 6JB, UK.
Correspondence and requests for materials should be addressed to
P.P.P. (p-pandolfi@ski.mskcc.org).
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.
© 2005 Nature Publishing Group
Source:
http://www.nature.com/cgi-taf/DynaPage.taf?file=/nature/journal/v433/n7023/abs/nature03203_fs.html
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Supplementary
Figure S1
The
protein expression levels of introduced oncogenes. (JPG; 25K)
http://www.nature.com/nature/journal/v433/n7023/extref/nature03203-s1.jpg
Supplementary
Figure S2
Identification of Pokemon binding sequence. (JPG; 65K)
http://www.nature.com/nature/journal/v433/n7023/extref/nature03203-s2.jpg
Supplementary
Figure S3
Schematic representations of the ARF promoter. (JPG; 97K)
http://www.nature.com/nature/journal/v433/n7023/extref/nature03203-s3.jpg
Supplementary
Figure S4
The expression levels of Pokemon mRNA in transgenic founder
lines. (JPG; 29K)
http://www.nature.com/nature/journal/v433/n7023/extref/nature03203-s4.jpg
Supplementary
Figure S5
POKEMON expression in human and mouse normal lymphoid tissues. (JPG;
86K)
http://www.nature.com/nature/journal/v433/n7023/extref/nature03203-s5.jpg
Supplementary
Figure S6
Kaplan-Meier curves for various prognostic markers. (JPG; 75K)
http://www.nature.com/nature/journal/v433/n7023/extref/nature03203-s6.jpg
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; 45K)
http://www.nature.com/nature/journal/v433/n7023/extref/nature03203-s7.doc
Supplementary
Figure Legends
Legends to accompany the above Supplementary Figures. (DOC; 58K)
http://www.nature.com/nature/journal/v433/n7023/extref/nature03203-s8.doc
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;
43K)
http://www.nature.com/nature/journal/v433/n7023/extref/nature03203-s9.doc
© 2005 Nature Publishing Group
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