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- Title
Expression of dominant negative Jun inhibits elevated AP-1 and NF-κB transactivation and suppresses anchorage independent growth of HPV immortalized human keratinocytes.
- Authors
Li, Jian-Jian; Rhim, Johng S; Schlegel, Richard; Vousden, Karen H; Colburn, Nancy H
- Abstract
AP-1 transactivation appears to be required for mouse JB6 cell neoplastic transformation induced by the tumor promoter TPA or epidermal growth factor (EGF). Exposure to AP-1 transrepressing retinoids and glucocorticoids and expression of a dominant negative c-jun (TAM67) blocked tumor promoter-induced AP-1 transactivation and neoplastic transformation. The aim of the present study was to extend the inquiry of the role of AP-1 and other transcription factors to human neoplastic progression. Expression of human papillomavirus (HPV) 16 or 18 E6 and E7 immortalizes human keratinocytes and inhibits serum/calcium-stimulated differentiation. Further transformation by v-fos co-expression renders these keratinocytes tumorigenic in nude mice. We have analysed two series of E6/E7 immortalized human keratinocyte cell lines that show progressing phenotypes ranging from differentiation sensitive to anchorage-independent to tumorigenic in nude mice. We analysed the activities of AP-1 and NF-κB which may `cross-talk'. Both DNA binding and transactivation of AP-1 and NF-κB transcription factors showed elevation in the anchorage-independent (16RH) and tumorigenic (18 v-fos) keratinocyte lines compared to the less progressed but immortalized cell lines. HPV E7 was expressed at a constant level shown by quantitative RT-PCR in both the more and the less progressed lines, indicating that E7 is not the factor limiting this progression. Blocked shift/supershift analysis indicates that Fos family member proteins especially Fra-1 and Fra-2 are related to progression and no changes found in the Jun family member proteins although they are present in the AP-1/DNA binding complex. When a dominant negative mutant c-jun driven by a human keratin 14 promoter was co-transfected with AP-1 or NF-κB reporters, both AP-1 and NF-κB activities were suppressed in the more progressed cell lines 16RH and 18 v-fos but not in the less progressed 16RL or 18 cell lines. Overexpression...
- Subjects
TRANSCRIPTION factors; CARCINOGENESIS
- Publication
Oncogene, 1998, Vol 16, Issue 21, p2711
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1201798