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p53-independent mechanisms regulate the P2-MDM2 promoter in adult astrocytic tumours
The MDM2 gene is amplified and/or overexpressed in about 10% of glioblastomas and constitutes one of a number of ways the p53 pathway is disrupted in these tumours. MDM2 encodes a nuclear phosphoprotein that regulates several cell proteins by binding and/or ubiquitinating them, with p53 being a well...
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Published in: | British journal of cancer 2008-10, Vol.99 (7), p.1144-1152 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | The
MDM2
gene is amplified and/or overexpressed in about 10% of glioblastomas and constitutes one of a number of ways the p53 pathway is disrupted in these tumours.
MDM2
encodes a nuclear phosphoprotein that regulates several cell proteins by binding and/or ubiquitinating them, with p53 being a well-established partner.
MDM2
has two promoters, P1 and P2 that give rise to transcripts with distinct 5′ untranslated regions. Transcription from P2 is believed to be controlled by p53 and a single-nucleotide polymorphism (SNP309, T>G) in P2 is reported to be associated with increased risk for, and early development of, malignancies. The use of P1 and P2 has not been investigated in gliomas. We used RT–PCR to study P1- and P2-MDM2 transcript expression in astrocytic tumours, xenografts and cell lines with known
MDM2
,
TP53
and
p14
ARF
gene status. Both promoters were used in all genetic backgrounds including the use of the P2 promoter in
TP53
null cells, indicating a p53-independent induction of transcription. Transcripts from the P1 promoter formed a greater proportion of the total
MDM2
transcripts in tumours with
MDM
2 amplification, despite these tumours having two wild-type
TP53
alleles. Examination of SNP309 in glioblastoma patients showed a borderline association with survival but no apparent correlation with age at diagnosis nor with
TP53
and
p14
ARF
status of their tumours. Our findings also indicate that elevated MDM2 mRNA levels in tumours with
MDM2
amplification are preferentially driven by the P1 promoter and that the P2 promoter is not only regulated by p53 but also by other transcription factor(s). |
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ISSN: | 0007-0920 1532-1827 1532-1827 |
DOI: | 10.1038/sj.bjc.6604643 |