Overexpressed TP73 induces apoptosis in medulloblastoma
<p>Abstract</p> <p>Background</p> <p>Medulloblastoma is the most common malignant brain tumor of childhood. Children who relapse usually die of their disease, which reflects resistance to radiation and/or chemotherapy. Improvements in outcome require a better understand...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2007-07-01
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| Series: | BMC Cancer |
| Online Access: | http://www.biomedcentral.com/1471-2407/7/127 |
| _version_ | 1819121974932144128 |
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| author | Perlaky Laszlo Adesina Adekunle M Rajan Jessen A Skapura Darlene G Lin Linda L De Bortoli Massimiliano Castellino Robert C Irwin Meredith S Kim John YH |
| author_facet | Perlaky Laszlo Adesina Adekunle M Rajan Jessen A Skapura Darlene G Lin Linda L De Bortoli Massimiliano Castellino Robert C Irwin Meredith S Kim John YH |
| author_sort | Perlaky Laszlo |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Medulloblastoma is the most common malignant brain tumor of childhood. Children who relapse usually die of their disease, which reflects resistance to radiation and/or chemotherapy. Improvements in outcome require a better understanding of the molecular basis of medulloblastoma growth and treatment response. <it>TP73 </it>is a member of the <it>TP53 </it>tumor suppressor gene family that has been found to be overexpressed in a variety of tumors and mediates apoptotic responses to genotoxic stress. In this study, we assessed expression of <it>TP73 </it>RNA species in patient tumor specimens and in medulloblastoma cell lines, and manipulated expression of full-length TAp73 and amino-terminal truncated ΔNp73 to assess their effects on growth.</p> <p>Methods</p> <p>We analyzed medulloblastoma samples from thirty-four pediatric patients and the established medulloblastoma cell lines, Daoy and D283MED, for expression of <it>TP73 </it>RNA including the full-length transcript and the 5'-terminal variants that encode the ΔNp73 isoform, as well as <it>TP53 </it>RNA using quantitative real time-RTPCR. Protein expression of TAp73 and ΔNp73 was quantitated with immunoblotting methods. Clinical outcome was analyzed based on <it>TP73 </it>RNA and p53 protein expression. To determine effects of overexpression or knock-down of TAp73 and ΔNp73 on cell cycle and apoptosis, we analyzed transiently transfected medulloblastoma cell lines with flow cytometric and TUNEL methods.</p> <p>Results</p> <p>Patient medulloblastoma samples and cell lines expressed full-length and 5'-terminal variant <it>TP73 </it>RNA species in 100-fold excess compared to non-neoplastic brain controls. Western immunoblot analysis confirmed their elevated levels of TAp73 and amino-terminal truncated ΔNp73 proteins. Kaplan-Meier analysis revealed trends toward favorable overall and progression-free survival of patients whose tumors display TAp73 RNA overexpression. Overexpression of TAp73 or ΔNp73 induced apoptosis under basal growth conditions <it>in vitro </it>and sensitized them to cell death in response to chemotherapeutic agents.</p> <p>Conclusion</p> <p>These results indicate that primary medulloblastomas express significant levels of <it>TP73 </it>isoforms, and suggest that they can modulate the survival and genotoxic responsiveness of medulloblastomas cells.</p> |
| first_indexed | 2024-12-22T06:45:05Z |
| format | Article |
| id | doaj.art-80745cf801334aeda9e9484f4d3b26af |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-22T06:45:05Z |
| publishDate | 2007-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-80745cf801334aeda9e9484f4d3b26af2022-12-21T18:35:18ZengBMCBMC Cancer1471-24072007-07-017112710.1186/1471-2407-7-127Overexpressed TP73 induces apoptosis in medulloblastomaPerlaky LaszloAdesina Adekunle MRajan Jessen ASkapura Darlene GLin Linda LDe Bortoli MassimilianoCastellino Robert CIrwin Meredith SKim John YH<p>Abstract</p> <p>Background</p> <p>Medulloblastoma is the most common malignant brain tumor of childhood. Children who relapse usually die of their disease, which reflects resistance to radiation and/or chemotherapy. Improvements in outcome require a better understanding of the molecular basis of medulloblastoma growth and treatment response. <it>TP73 </it>is a member of the <it>TP53 </it>tumor suppressor gene family that has been found to be overexpressed in a variety of tumors and mediates apoptotic responses to genotoxic stress. In this study, we assessed expression of <it>TP73 </it>RNA species in patient tumor specimens and in medulloblastoma cell lines, and manipulated expression of full-length TAp73 and amino-terminal truncated ΔNp73 to assess their effects on growth.</p> <p>Methods</p> <p>We analyzed medulloblastoma samples from thirty-four pediatric patients and the established medulloblastoma cell lines, Daoy and D283MED, for expression of <it>TP73 </it>RNA including the full-length transcript and the 5'-terminal variants that encode the ΔNp73 isoform, as well as <it>TP53 </it>RNA using quantitative real time-RTPCR. Protein expression of TAp73 and ΔNp73 was quantitated with immunoblotting methods. Clinical outcome was analyzed based on <it>TP73 </it>RNA and p53 protein expression. To determine effects of overexpression or knock-down of TAp73 and ΔNp73 on cell cycle and apoptosis, we analyzed transiently transfected medulloblastoma cell lines with flow cytometric and TUNEL methods.</p> <p>Results</p> <p>Patient medulloblastoma samples and cell lines expressed full-length and 5'-terminal variant <it>TP73 </it>RNA species in 100-fold excess compared to non-neoplastic brain controls. Western immunoblot analysis confirmed their elevated levels of TAp73 and amino-terminal truncated ΔNp73 proteins. Kaplan-Meier analysis revealed trends toward favorable overall and progression-free survival of patients whose tumors display TAp73 RNA overexpression. Overexpression of TAp73 or ΔNp73 induced apoptosis under basal growth conditions <it>in vitro </it>and sensitized them to cell death in response to chemotherapeutic agents.</p> <p>Conclusion</p> <p>These results indicate that primary medulloblastomas express significant levels of <it>TP73 </it>isoforms, and suggest that they can modulate the survival and genotoxic responsiveness of medulloblastomas cells.</p>http://www.biomedcentral.com/1471-2407/7/127 |
| spellingShingle | Perlaky Laszlo Adesina Adekunle M Rajan Jessen A Skapura Darlene G Lin Linda L De Bortoli Massimiliano Castellino Robert C Irwin Meredith S Kim John YH Overexpressed TP73 induces apoptosis in medulloblastoma BMC Cancer |
| title | Overexpressed TP73 induces apoptosis in medulloblastoma |
| title_full | Overexpressed TP73 induces apoptosis in medulloblastoma |
| title_fullStr | Overexpressed TP73 induces apoptosis in medulloblastoma |
| title_full_unstemmed | Overexpressed TP73 induces apoptosis in medulloblastoma |
| title_short | Overexpressed TP73 induces apoptosis in medulloblastoma |
| title_sort | overexpressed tp73 induces apoptosis in medulloblastoma |
| url | http://www.biomedcentral.com/1471-2407/7/127 |
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