title: p53-independent mechanisms regulate the P2-MDM2 promoter in adult astrocytic tumours.
abstract: 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 MDM2 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).
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Box 231, Cambridge CB2 0QQ, UK. mdimitriadi@cantab.net
authors.forename: M
authors.initials: M
authors.lastname: Dimitriadi
authors.forename: G
authors.initials: G
authors.lastname: Poulogiannis
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: L M
authors.initials: LM
authors.lastname: Bäcklund
authors.forename: D M
authors.initials: DM
authors.lastname: Pearson
authors.forename: K
authors.initials: K
authors.lastname: Ichimura
authors.forename: V P
authors.initials: VP
authors.lastname: Collins
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000235:genetics*; D005838:Genotype; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
references.citation: J Neuropathol Exp Neurol. 1999 Nov;58(11):1170-83
references.pmid: 10560660
references.citation: Cancer Res. 1993 Jun 15;53(12):2736-9
references.pmid: 8504413
references.citation: J Biol Chem. 2004 Jul 9;279(28):29841-8
references.pmid: 15090541
references.citation: Int Rev Exp Pathol. 1983;24:135-202
references.pmid: 6601641
references.citation: Nature. 1997 May 15;387(6630):299-303
references.pmid: 9153396
references.citation: Genes Dev. 2005 Sep 15;19(18):2122-37
references.pmid: 16131611
references.citation: Oral Oncol. 2001 Dec;37(8):620-31
references.pmid: 11590071
references.citation: Neurol Med Chir (Tokyo). 2007 May;47(5):203-8; discussion 208-9
references.pmid: 17527046
references.citation: Clin Cancer Res. 2003 Sep 15;9(11):4151-8
references.pmid: 14519639
references.citation: Curr Cancer Drug Targets. 2005 Feb;5(1):9-20
references.pmid: 15720185
references.citation: Eur J Cancer. 1999 Jul;35(7):1083-8
references.pmid: 10533452
references.citation: Mol Cell Biol. 1999 Jan;19(1):864-72
references.pmid: 9858609
references.citation: Oncol Rep. 2002 May-Jun;9(3):557-63
references.pmid: 11956627
references.citation: Mol Cancer Res. 2003 Dec;1(14):1017-26
references.pmid: 14707285
references.citation: J Neurooncol. 2007 Dec;85(3):241-4
references.pmid: 17568997
references.citation: Oncogene. 2002 Mar 27;21(13):1955-62
references.pmid: 11960368
references.citation: J Mol Med (Berl). 2005 Nov;83(11):917-26
references.pmid: 16133418
references.citation: Leukemia. 2005 Nov;19(11):1996-8
references.pmid: 16167062
references.citation: Cancer Res. 1997 Aug 15;57(16):3562-8
references.pmid: 9270029
references.citation: Cell. 2004 Nov 24;119(5):591-602
references.pmid: 15550242
references.citation: Int J Cancer. 2007 Feb 1;120(3):563-5
references.pmid: 17096342
references.citation: Oncogene. 2000 Feb 10;19(6):831-5
references.pmid: 10698502
references.citation: Clin Cancer Res. 2007 Jun 1;13(11):3215-20
references.pmid: 17545525
references.citation: Anticancer Res. 2006 Nov-Dec;26(6C):4975-7
references.pmid: 17214373
references.citation: Acta Neuropathol. 2007 Aug;114(2):97-109
references.pmid: 17618441
references.citation: Nucleic Acids Res. 1998 Aug 1;26(15):3453-9
references.pmid: 9671804
references.citation: Cell. 2000 Oct 13;103(2):321-30
references.pmid: 11057904
references.citation: Cell. 1992 Jun 26;69(7):1237-45
references.pmid: 1535557
references.citation: Oncogene. 2006 Jul 13;25(30):4183-93
references.pmid: 16501602
references.citation: Mol Cell Biol. 2000 Mar;20(6):2023-30
references.pmid: 10688649
references.citation: Oncogene. 2001 May 31;20(25):3193-205
references.pmid: 11423969
references.citation: Cancer Cell. 2007 Oct;12(4):303-12
references.pmid: 17936556
references.citation: Genes Chromosomes Cancer. 2005 Jun;43(2):181-93
references.pmid: 15770670
references.citation: Nucleic Acids Res. 1995 Jul 25;23(14):2584-92
references.pmid: 7651818
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8292-7
references.pmid: 9653180
references.citation: J Biol Chem. 2003 Jul 11;278(28):25716-21
references.pmid: 12730202
references.citation: Oncogene. 2007 Feb 26;26(9):1317-23
references.pmid: 17322917
references.citation: J Biol Chem. 2005 Apr 29;280(17):16651-8
references.pmid: 15723837
references.citation: Int J Cancer. 2000 May 20;89(3):265-70
references.pmid: 10861503
references.citation: Oncogene. 1996 Sep 5;13(5):1065-72
references.pmid: 8806696
references.citation: Cancer Res. 1998 Nov 15;58(22):5061-5
references.pmid: 9823311
references.citation: Brain Res. 2008 Mar 10;1198:16-20
references.pmid: 18262501
references.citation: Mol Cell Biol. 2004 Apr;24(8):3536-51
references.pmid: 15060172
references.citation: Cancer Res. 2001 Feb 15;61(4):1598-603
references.pmid: 11245471
references.citation: Cancer Res. 2005 Oct 15;65(20):9582-7
references.pmid: 16230424
references.citation: Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14517-22
references.pmid: 10588737
references.citation: Cancer Lett. 2006 Aug 28;240(2):195-7
references.pmid: 16239061
references.citation: Leuk Lymphoma. 1995 Mar;17(1-2):13-8
references.pmid: 7773150
references.citation: Cancer Lett. 2001 Mar 26;164(2):177-88
references.pmid: 11179833
references.citation: Oncogene. 2008 Mar 27;27(14):2097-108
references.pmid: 17934521
references.citation: Genes Dev. 1994 Aug 1;8(15):1739-49
references.pmid: 7958853
references.citation: Am J Pathol. 2000 Aug;157(2):587-96
references.pmid: 10934161
references.citation: Cancer Res. 2000 Jan 15;60(2):417-24
references.pmid: 10667596
references.citation: Cancer Res. 2003 May 15;63(10):2616-23
references.pmid: 12750288
references.citation: Nature. 1997 May 15;387(6630):296-9
references.pmid: 9153395
references.citation: Cancer Epidemiol Biomarkers Prev. 2006 Aug;15(8):1559-61
references.pmid: 16896050
references.citation: Oncogene. 1998 Apr 30;16(17):2249-57
references.pmid: 9619834
references.citation: Clin Cancer Res. 2005 Feb 1;11(3):1119-28
references.pmid: 15709179