title: Glioma tumor grade correlates with parkin depletion in mutant p53-linked tumors and results from loss of function of p53 transcriptional activity.
abstract: 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.
authors: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA, team labeled 'Fondation pour la Recherche Médicale' and 'Laboratory of Excellence (LABEX) Distalz', Valbonne, France.
authors: J
authors: J
authors: Viotti
authors: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA, team labeled 'Fondation pour la Recherche Médicale' and 'Laboratory of Excellence (LABEX) Distalz', Valbonne, France.
authors: E
authors: E
authors: Duplan
authors: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA, team labeled 'Fondation pour la Recherche Médicale' and 'Laboratory of Excellence (LABEX) Distalz', Valbonne, France.
authors: C
authors: C
authors: Caillava
authors: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA, team labeled 'Fondation pour la Recherche Médicale' and 'Laboratory of Excellence (LABEX) Distalz', Valbonne, France.
authors: J
authors: J
authors: Condat
authors: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA, team labeled 'Fondation pour la Recherche Médicale' and 'Laboratory of Excellence (LABEX) Distalz', Valbonne, France.
authors: T
authors: T
authors: Goiran
authors: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA, team labeled 'Fondation pour la Recherche Médicale' and 'Laboratory of Excellence (LABEX) Distalz', Valbonne, France.
authors: C
authors: C
authors: Giordano
authors: AP-HP, Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre & Marie Curie Paris VI, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, UMRS 975, Paris, France.
authors: Y
authors: Y
authors: Marie
authors: AP-HP, Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre & Marie Curie Paris VI, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, UMRS 975, Paris, France.
authors: A
authors: A
authors: Idbaih
authors: AP-HP, Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre & Marie Curie Paris VI, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, UMRS 975, Paris, France.
authors: J-Y
authors: JY
authors: Delattre
authors: 1] Centre de référence des maladies rares «syndromes neurologiques paranéoplasiques», hospices civils de Lyon, hôpital neurologique, Lyon, France [2] Inserm U1028/CNRS UMR 5292, centre de recherche en neuroscience de Lyon, Lyon, France [3] Université de Lyon, Université Claude-Bernard Lyon-1, Lyon, France.
authors: J
authors: J
authors: Honnorat
authors: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA, team labeled 'Fondation pour la Recherche Médicale' and 'Laboratory of Excellence (LABEX) Distalz', Valbonne, France.
authors: F
authors: F
authors: Checler
authors: Institut de Pharmacologie Moléculaire et Cellulaire, UMR7275 CNRS/UNSA, team labeled 'Fondation pour la Recherche Médicale' and 'Laboratory of Excellence (LABEX) Distalz', Valbonne, France.
authors: C
authors: C
authors: Alves da Costa
mesh_terms: D000483:Alleles; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009837:Oligodendroglioma / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000502:physiology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein