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Increased E2F1 activity induces skin tumors in mice heterozygous and nullizygous for p53
A M Pierce1, I B Gimenez-Conti, R Schneider-Broussard
1University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Department of Carcinogenesis, Smithville, TX 78957, USA.
Abstract:
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.
Insights
The p16(INK4a)-cyclin D-retinoblastoma tumor suppressor pathway is crucial in cancer. Increased E2F1 expression drives skin cancer in mice lacking p53, highlighting p53
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The p16(INK4a)-cyclin D-retinoblastoma tumor suppressor pathway is frequently disrupted in human cancers.
- E2F transcription factors, when released from inhibitory complexes, are implicated in tumor development.
- Previous work generated transgenic mice with keratin 5 (K5) promoter-driven E2F1 expression in squamous epithelial tissues.
Purpose of the Study:
- To investigate the in vivo functional interactions between E2F1 and p53.
- To determine the role of p53 in E2F1-mediated cellular responses and tumor development.
Main Methods:
- Crossed K5 E2F1 transgenic mice with p53 null mice.
- Analyzed E2F1-induced apoptosis and hyperproliferation in epidermal keratinocytes.
- Assessed spontaneous skin tumor development in mice with varying p53 and E2F1 expression levels.
- Examined E2F1 DNA-binding activity and cyclin E expression/kinase activity in primary transgenic keratinocytes.
Main Results:
- E2F1-induced apoptosis of epidermal keratinocytes was reduced in p53-deficient K5 E2F1 transgenic mice.
- E2F1-induced hyperproliferation was not affected by p53 status.
- K5 E2F1 transgenic mice lacking or heterozygous for p53 developed spontaneous skin carcinomas.
- Tumor development timing correlated with E2F1 expression levels and p53 status.
- Elevated cyclin E expression and kinase activity were observed in transgenic keratinocytes.
Conclusions:
- Increased E2F1 expression contributes to tumor development.
- p53 plays a critical role in eliminating cells with deregulated E2F1 activity.
- The interplay between E2F1 and p53 is vital in preventing skin cancer.