Evasion of Cell Senescence Leads to Medulloblastoma Progression
| Autor: | Lukas Tamayo-Orrego, Chia-Lun Wu, Frédéric Charron, Nicolas Bouchard, Patryk Skowron, Michael D. Taylor, Marc Remke, Ahmed Khedher, Shannon M. Swikert |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
p53 p16ink4a Somatic cell Cell Loss of Heterozygosity Kaplan-Meier Estimate Loss of heterozygosity Mice CDKN2A Cerebellum Sonic hedgehog Promoter Regions Genetic lcsh:QH301-705.5 Cellular Senescence biology Brain Neoplasms Immunohistochemistry 3. Good health Patched-1 Receptor ptch1 medicine.anatomical_structure Disease Progression Senescence endocrine system Ultraviolet Rays Mutation Missense preneoplasia General Biochemistry Genetics and Molecular Biology 03 medical and health sciences sonic hedgehog medicine Animals Humans Hedgehog Proteins neoplasms Cyclin-Dependent Kinase Inhibitor p16 Medulloblastoma DNA Methylation medicine.disease Mice Inbred C57BL stomatognathic diseases 030104 developmental biology PTCH1 lcsh:Biology (General) Microscopy Fluorescence biology.protein Cancer research Tumor Suppressor Protein p53 |
| Zdroj: | Cell Reports, Vol 14, Iss 12, Pp 2925-2937 (2016) |
| ISSN: | 2211-1247 |
| Popis: | Summary How brain tumors progress from precancerous lesions to advanced cancers is not well understood. Using Ptch1 +/− mice to study medulloblastoma progression, we found that Ptch1 loss of heterozygosity (LOH) is an early event that is associated with high levels of cell senescence in preneoplasia. In contrast, advanced tumors have evaded senescence. Remarkably, we discovered that the majority of advanced medulloblastomas display either spontaneous, somatic p53 mutations or Cdkn2a locus inactivation. Consistent with senescence evasion, these p53 mutations are always subsequent to Ptch1 LOH. Introduction of a p53 mutation prevents senescence, accelerates tumor formation, and increases medulloblastoma incidence. Altogether, our results show that evasion of senescence associated with Ptch1 LOH allows progression to advanced tumors. |
| Databáze: | OpenAIRE |
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