Increased E2F1 activity induces skin tumors in mice heterozygous and nullizygous for p53.
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.
Pierce
A M
AM
University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Department of Carcinogenesis, Smithville, TX 78957, USA.
Gimenez-Conti
I B
IB
Schneider-Broussard
R
R
Martinez
L A
LA
Conti
C J
CJ
Johnson
D G
DG
D000818:Animals; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D006579:Heterozygote; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D056465:Retinoblastoma-Binding Protein 1; D012878:Skin Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53