Increased E2F1 activity induces skin tumors in mice heterozygous and nullizygous for p53
| Autor: | Claudio J. Conti, Luis Arboledas Martínez, Irma B. Gimenez-Conti, David G. Johnson, Robin Schneider-Broussard, Angela M. Pierce |
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| Rok vydání: | 1998 |
| Předmět: |
Genetically modified mouse
Keratinocytes endocrine system Heterozygote Cyclin E Skin Neoplasms Transgene Cell Cycle Proteins Mice Transgenic Biology Mice medicine E2F1 Animals Kinase activity E2F Mice Knockout Multidisciplinary Retinoblastoma Biological Sciences medicine.disease E2F Transcription Factors Up-Regulation Keratin 5 DNA-Binding Proteins Phenotype Cancer research biological phenomena cell phenomena and immunity Tumor Suppressor Protein p53 Carrier Proteins Transcription Factor DP1 E2F1 Transcription Factor Retinoblastoma-Binding Protein 1 Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 95(15) |
| ISSN: | 0027-8424 |
| Popis: | The p16 INK4a -cyclin D–retinoblastoma tumor suppressor pathway is disrupted in most human cancers, and it has been suggested that the subsequent release of E2F transcription factors from inhibitory complexes may be a key event in tumor development. We described recently the generation of transgenic mice with E2F1 gene expression targeted to squamous epithelial tissues by a keratin 5 (K5) promoter. In the present study, K5 E2F1 transgenic mice were crossed with p53 null mice to examine functional interactions between E2F1 and p53 in vivo. We find that E2F1-induced apoptosis of epidermal keratinocytes is reduced in K5 E2F1 transgenic mice lacking p53, whereas E2F1-induced hyperproliferation is unaffected by p53 status. We also find that K5 E2F1 transgenic mice heterozygous or nullizygous for p53 develop spontaneous skin carcinomas, which normally are rare in p53-deficient mice. The timing of tumor development correlates with the level of E2F1 transgene expression and the status of p53. In primary transgenic keratinocytes, the major change in E2F1 DNA-binding activity is the generation of a complex also containing the retinoblastoma tumor suppressor protein. Nevertheless, the expression and associated kinase activity of cyclin E, a known target for E2F transcriptional activity, is elevated significantly in K5 E2F1 transgenic keratinocytes. These findings firmly establish that increased E2F1 expression can contribute to tumor development and suggest that p53 plays an important role in eliminating cells with deregulated E2F1 activity. |
| Databáze: | OpenAIRE |
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