Glioma tumor grade correlates with parkin depletion in mutant p53-linked tumors and results from loss of function of p53 transcriptional activity

被引:57
作者
Viotti, J. [1 ]
Duplan, E. [1 ]
Caillava, C. [1 ]
Condat, J. [1 ]
Goiran, T. [1 ]
Giordano, C. [1 ]
Marie, Y. [2 ]
Idbaih, A. [2 ]
Delattre, J-Y [2 ]
Honnorat, J. [3 ,4 ,5 ]
Checler, F. [1 ]
Alves Da Costa, C. [1 ]
机构
[1] CNRS, Inst Pharmacol Mol & Cellulaire, UNSA, Team Labeled Fdn,Rech Med & Lab Excellemce LABEX, F-06560 Valbonne, France
[2] Univ Paris 06, AP HP, Grp Hosp Pitie Salpetriere,UMR 975, Ctr Rech,Inst Cerveau & Moelle Epiniere,Serv Neur, Paris, France
[3] Hop Neurol, Hosp Civils Lyon, Ctr Reference Maladies Rares Syndromes Neurol Par, Lyon, France
[4] Ctr Rech Neurosci Lyon, Inserm U1028, CNRS UMR 5292, Lyon, France
[5] Univ Lyon 1, Univ Lyon, F-69365 Lyon, France
关键词
human brain glioma; glioblastoma cells; tumor grade; parkin; p53; transcription; SUPPRESSOR GENE; HEPATOCELLULAR-CARCINOMA; CELL-PROLIFERATION; BRAIN-TUMORS; BAX GENE; IN-VITRO; MUTATIONS; PROTEIN; CANCER; EXPRESSION;
D O I
10.1038/onc.2013.124
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Gliomas represent the most frequent form of primary brain tumors in adults, the prognosis of which remains extremely poor. Inactivating mutations on the tumor suppressor TP53 were proposed as a key etiological trigger of glioma development. p53 has been recently identified as a transcriptional target of parkin. Interestingly, somatic mutations on parkin have also been linked to glioma genesis. We examined the possibility that a disruption of a functional interaction between p53 and parkin could contribute to glioma development in samples devoid of somatic parkin mutations or genetic allele deletion. We show here that parkin levels inversely correlate to brain tumor grade and p53 levels in oligodendrogliomas, mixed gliomas and glioblastomas. We demonstrate that p53 levels negatively and positively correlate to bax and Bcl2 respectively, underlying a loss of p53 transcriptional activity in all types of glial tumors. Using various cell models lacking p53 or harboring either transcriptionally inactive or dominant negative p53, as well as in p53 knockout mice brain, we establish that p53 controls parkin promoter transactivation, mRNA and protein levels. Furthermore, we document an increase of parkin expression in mice brain after p53-bearing viral infection. Finally, both cancer-related p53 inactivating mutations and deletion of a consensus p53 binding sequence located on parkin promoter abolish p53-mediated control of parkin transcription, demonstrating that p53 regulates parkin transcription via its DNA binding properties. In conclusion, our work delineates a functional interplay between mutated p53 and parkin in glioma genesis that is disrupted by cancer-linked pathogenic mutations. It also allows envisioning parkin as a novel biomarker of glioma biopsies enabling to follow the progression of this type of cancers.
引用
收藏
页码:1764 / 1775
页数:12
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