Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic Slippage
Tumor suppressor p53 is a major cellular guardian of genome integrity, and its inactivation is the most frequent genetic alteration in cancer, rising up to 80% in squamous cell carcinoma (SCC). By adapting the small hairpin RNA (shRNA) technology, we inactivated endogenous p53 in primary epithelial...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2014-11-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124714008663 |
| _version_ | 1828791741129424896 |
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| author | Ana Freije Rut Molinuevo Laura Ceballos Marta Cagigas Pilar Alonso-Lecue René Rodriguez Pablo Menendez Daniel Aberdam Ernesto De Diego Alberto Gandarillas |
| author_facet | Ana Freije Rut Molinuevo Laura Ceballos Marta Cagigas Pilar Alonso-Lecue René Rodriguez Pablo Menendez Daniel Aberdam Ernesto De Diego Alberto Gandarillas |
| author_sort | Ana Freije |
| collection | DOAJ |
| description | Tumor suppressor p53 is a major cellular guardian of genome integrity, and its inactivation is the most frequent genetic alteration in cancer, rising up to 80% in squamous cell carcinoma (SCC). By adapting the small hairpin RNA (shRNA) technology, we inactivated endogenous p53 in primary epithelial cells from the epidermis of human skin. We show that either loss of endogenous p53 or overexpression of a temperature-sensitive dominant-negative conformation triggers a self-protective differentiation response, resulting in cell stratification and expulsion. These effects follow DNA damage and exit from mitosis without cell division. p53 preserves the proliferative potential of the stem cell compartment and limits the power of proto-oncogene MYC to drive cell cycle stress and differentiation. The results provide insight into the role of p53 in self-renewal homeostasis and help explain why p53 mutations do not initiate skin cancer but increase the likelihood that cancer cells will appear. |
| first_indexed | 2024-12-12T02:56:12Z |
| format | Article |
| id | doaj.art-e0eb7951ac3e478896bd90c1eccf866c |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-12T02:56:12Z |
| publishDate | 2014-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-e0eb7951ac3e478896bd90c1eccf866c2022-12-22T00:40:46ZengElsevierCell Reports2211-12472014-11-01941349136010.1016/j.celrep.2014.10.012Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic SlippageAna Freije0Rut Molinuevo1Laura Ceballos2Marta Cagigas3Pilar Alonso-Lecue4René Rodriguez5Pablo Menendez6Daniel Aberdam7Ernesto De Diego8Alberto Gandarillas9Cell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, SpainCell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, SpainCell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, SpainCell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, SpainCell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, SpainLab 2-ORL, Instituto Universitario de Oncología de Asturias (IUOPA) Hospital Universitario Central de Asturias (HUCA), Oviedo 33006, SpainJosep Carreras Leukaemia Research Institute, School of Medicine, University of Barcelona, Barcelona 08036, SpainINSERM UMR-S976, University Paris Didero, Hôpital Saint-Louis, Equerre Bazin, Paris 75475, FranceCell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, SpainCell Cycle, Stem Cell Fate and Cancer Laboratory, Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander 39011, SpainTumor suppressor p53 is a major cellular guardian of genome integrity, and its inactivation is the most frequent genetic alteration in cancer, rising up to 80% in squamous cell carcinoma (SCC). By adapting the small hairpin RNA (shRNA) technology, we inactivated endogenous p53 in primary epithelial cells from the epidermis of human skin. We show that either loss of endogenous p53 or overexpression of a temperature-sensitive dominant-negative conformation triggers a self-protective differentiation response, resulting in cell stratification and expulsion. These effects follow DNA damage and exit from mitosis without cell division. p53 preserves the proliferative potential of the stem cell compartment and limits the power of proto-oncogene MYC to drive cell cycle stress and differentiation. The results provide insight into the role of p53 in self-renewal homeostasis and help explain why p53 mutations do not initiate skin cancer but increase the likelihood that cancer cells will appear.http://www.sciencedirect.com/science/article/pii/S2211124714008663 |
| spellingShingle | Ana Freije Rut Molinuevo Laura Ceballos Marta Cagigas Pilar Alonso-Lecue René Rodriguez Pablo Menendez Daniel Aberdam Ernesto De Diego Alberto Gandarillas Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic Slippage Cell Reports |
| title | Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic Slippage |
| title_full | Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic Slippage |
| title_fullStr | Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic Slippage |
| title_full_unstemmed | Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic Slippage |
| title_short | Inactivation of p53 in Human Keratinocytes Leads to Squamous Differentiation and Shedding via Replication Stress and Mitotic Slippage |
| title_sort | inactivation of p53 in human keratinocytes leads to squamous differentiation and shedding via replication stress and mitotic slippage |
| url | http://www.sciencedirect.com/science/article/pii/S2211124714008663 |
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