Deregulated expression of E2F1 induces hyperplasia and cooperates with ras in skin tumor development.
In cell culture studies, overexpression of the E2F1 transcription factor has been shown to stimulate proliferation, induce apoptosis, and cooperate with an activated ras gene to oncogenically transform primary rodent cells. To study the effect of increased E2F1 activity on epithelial growth and tumorigenesis in vivo, transgenic mice expressing E2F1 under the control of a keratin 5 (K5) promoter were generated. Expression of E2F1 in the epidermis results in hyperplasia but does not inhibit terminal differentiation. In a transgenic line expressing high levels of E2F1, mice have decreased hair growth likely as a result of aberrant apoptosis in developing hair follicles. Coexpression of a cyclin D1 transgene with E2F1 augments epidermal hyperplasia and further disrupts hair follicle development suggesting that hypophosphorylated Rb antagonizes the proliferative and apoptotic-promoting activities of E2F1. Finally, the E2F1 transgene is found to cooperate with a v-Ha-ras transgene to induce skin tumors in double transgenic animals. These findings confirm that many of the activities ascribed to E2F1 through in vitro studies can be reproduced in vivo and demonstrate for the first time that deregulated E2F activity can contribute to tumor development.
Pierce
A M
AM
The University of Texas MD Anderson Cancer Center, Department of Carcinogenesis, Smithville 78957, USA.
Fisher
S M
SM
Conti
C J
CJ
Johnson
D G
DG
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002352:Carrier Proteins; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002455:Cell Division; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004817:Epidermis / Q000473:pathology; D005786:Gene Expression Regulation; D011905:Genes, ras; D006197:Hair / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D007633:Keratins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D056465:Retinoblastoma-Binding Protein 1; D012867:Skin / Q000473:pathology*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection
C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D007633:Keratins