p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells
<p dir="ltr">The restoration of p53 has been suggested as a therapeutic approach in tumors. However, the timing of p53 restoration in relation to its efficacy during tumor progression still is unclear. We now show that the restoration of p53 in murine premalignant proliferating pinea...
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2023
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| _version_ | 1864513512731049984 |
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| author | Mohamad Harajly (18810850) |
| author2 | Hasan Zalzali (18810853) Zafar Nawaz (96166) Sandra E. Ghayad (7353428) Farah Ghamloush (9449144) Hussein Basma (18810856) Samiha Zainedin (18810859) Wissam Rabeh (18810862) Mark Jabbour (631068) Ayman Tawil (6442628) Danielle A. Badro (9155014) Gerard I. Evan (13984602) Raya Saab (7353425) |
| author2_role | author author author author author author author author author author author author |
| author_facet | Mohamad Harajly (18810850) Hasan Zalzali (18810853) Zafar Nawaz (96166) Sandra E. Ghayad (7353428) Farah Ghamloush (9449144) Hussein Basma (18810856) Samiha Zainedin (18810859) Wissam Rabeh (18810862) Mark Jabbour (631068) Ayman Tawil (6442628) Danielle A. Badro (9155014) Gerard I. Evan (13984602) Raya Saab (7353425) |
| author_role | author |
| dc.creator.none.fl_str_mv | Mohamad Harajly (18810850) Hasan Zalzali (18810853) Zafar Nawaz (96166) Sandra E. Ghayad (7353428) Farah Ghamloush (9449144) Hussein Basma (18810856) Samiha Zainedin (18810859) Wissam Rabeh (18810862) Mark Jabbour (631068) Ayman Tawil (6442628) Danielle A. Badro (9155014) Gerard I. Evan (13984602) Raya Saab (7353425) |
| dc.date.none.fl_str_mv | 2023-03-17T06:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1128/mcb.00747-15 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/p53_Restoration_in_Induction_and_Maintenance_of_Senescence_Differential_Effects_in_Premalignant_and_Malignant_Tumor_Cells/26021512 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Oncology and carcinogenesis Tumor suppression Tumor progression Premalignant tumors Invasive tumors Tumor reentry Neuroectodermal tumors DNA-damaging therapy |
| dc.title.none.fl_str_mv | p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">The restoration of p53 has been suggested as a therapeutic approach in tumors. However, the timing of p53 restoration in relation to its efficacy during tumor progression still is unclear. We now show that the restoration of p53 in murine premalignant proliferating pineal lesions resulted in cellular senescence, while p53 restoration in invasive pineal tumors did not. The effectiveness of p53 restoration was not dependent on p19Arf expression but showed an inverse correlation with Mdm2 expression. In tumor cells, p53 restoration became effective when paired with either DNA-damaging therapy or with nutlin, an inhibitor of p53-Mdm2 interaction. Interestingly, the inactivation of p53 after senescence resulted in reentry into the cell cycle and rapid tumor progression. The evaluation of a panel of human supratentorial primitive neuroectodermal tumors (sPNET) showed low activity of the p53 pathway. Together, these data suggest that the restoration of the p53 pathway has different effects in premalignant versus invasive pineal tumors, and that p53 activation needs to be continually sustained, as reversion from senescence occurs rapidly with aggressive tumor growth when p53 is lost again. Finally, p53 restoration approaches may be worth exploring in sPNET, where the p53 gene is intact but the pathway is inactive in the majority of examined tumors.</p><h2>Other Information</h2><p dir="ltr">Published in: Molecular and Cellular Biology<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1128/mcb.00747-15" target="_blank">https://dx.doi.org/10.1128/mcb.00747-15</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_8a3a02703f2e1c54746899f80f00a901 |
| identifier_str_mv | 10.1128/mcb.00747-15 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26021512 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor CellsMohamad Harajly (18810850)Hasan Zalzali (18810853)Zafar Nawaz (96166)Sandra E. Ghayad (7353428)Farah Ghamloush (9449144)Hussein Basma (18810856)Samiha Zainedin (18810859)Wissam Rabeh (18810862)Mark Jabbour (631068)Ayman Tawil (6442628)Danielle A. Badro (9155014)Gerard I. Evan (13984602)Raya Saab (7353425)Biological sciencesBiochemistry and cell biologyBiomedical and clinical sciencesOncology and carcinogenesisTumor suppressionTumor progressionPremalignant tumorsInvasive tumorsTumor reentryNeuroectodermal tumorsDNA-damaging therapy<p dir="ltr">The restoration of p53 has been suggested as a therapeutic approach in tumors. However, the timing of p53 restoration in relation to its efficacy during tumor progression still is unclear. We now show that the restoration of p53 in murine premalignant proliferating pineal lesions resulted in cellular senescence, while p53 restoration in invasive pineal tumors did not. The effectiveness of p53 restoration was not dependent on p19Arf expression but showed an inverse correlation with Mdm2 expression. In tumor cells, p53 restoration became effective when paired with either DNA-damaging therapy or with nutlin, an inhibitor of p53-Mdm2 interaction. Interestingly, the inactivation of p53 after senescence resulted in reentry into the cell cycle and rapid tumor progression. The evaluation of a panel of human supratentorial primitive neuroectodermal tumors (sPNET) showed low activity of the p53 pathway. Together, these data suggest that the restoration of the p53 pathway has different effects in premalignant versus invasive pineal tumors, and that p53 activation needs to be continually sustained, as reversion from senescence occurs rapidly with aggressive tumor growth when p53 is lost again. Finally, p53 restoration approaches may be worth exploring in sPNET, where the p53 gene is intact but the pathway is inactive in the majority of examined tumors.</p><h2>Other Information</h2><p dir="ltr">Published in: Molecular and Cellular Biology<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1128/mcb.00747-15" target="_blank">https://dx.doi.org/10.1128/mcb.00747-15</a></p>2023-03-17T06:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1128/mcb.00747-15https://figshare.com/articles/journal_contribution/p53_Restoration_in_Induction_and_Maintenance_of_Senescence_Differential_Effects_in_Premalignant_and_Malignant_Tumor_Cells/26021512CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/260215122023-03-17T06:00:00Z |
| spellingShingle | p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells Mohamad Harajly (18810850) Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Oncology and carcinogenesis Tumor suppression Tumor progression Premalignant tumors Invasive tumors Tumor reentry Neuroectodermal tumors DNA-damaging therapy |
| status_str | publishedVersion |
| title | p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells |
| title_full | p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells |
| title_fullStr | p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells |
| title_full_unstemmed | p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells |
| title_short | p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells |
| title_sort | p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells |
| topic | Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Oncology and carcinogenesis Tumor suppression Tumor progression Premalignant tumors Invasive tumors Tumor reentry Neuroectodermal tumors DNA-damaging therapy |