Abstract
Cross-coupling of active protein-1 tAP-1) and nuclear factor (NF)-κB has been reported. In the present study, we investigated the possibility that both of these two transcription factors might contribute to the process of tumor promoter-induced transformation. To establish a stable reporter cell system, two reporter genes were stably transfected into a JB6 mouse tumor promotion-sensitive (P+) cell line: a luciferase reporter controlled by a collagenase AP-1 sequence and a chloramphenicol acetyltransferase reporter controlled by an interleukin 6 NF-κB sequence. This double-reporter cell line maintained the phenotype of tumor promotion sensitivity and was able to report basal or induced AP-1 and NF-κB transactivation. The cytokine tumor promoter tumor necrosis factor (TNF)-α transactivated NF-κB and AP-1 for both DNA binding and transcriptional activity, Pyrrolidine dithiocarbamate, an antioxidant that acts as an NF-κB inhibitor, efficiently inhibited 12-O- tetradecanoylphorbol-13-acetate (TPA) or TNF-α induced NF-κB as well as AP- 1 transactivation and cell transformation, suggesting dependency of transformation on both transcription factors. The AP-1 transrepressing- retinoid SR11302 transrepressed AP-1 and cell transformation when these were TPA induced but not when TNF-α induced, indicating different signaling pathways for TNF-α and TPA. Supershift electrophoresis mobility shift assay revealed that Jun B and c-Jun were absent from the AP-1/DNA complex following TNF-α but present following TPA treatment. Together, these results suggest that both AP-1 and NF-κB activation may be required for transformation whether induced by TPA or by TNF, and the differential sensitivity of TPA and TNF-α-induced transformation to inhibition by a retinoid might be explained by differences in the composition of the DNA-bound AP-1 complexes.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3569-3576 |
| Number of pages | 8 |
| Journal | Cancer Research |
| Volume | 57 |
| Issue number | 16 |
| State | Published - Aug 15 1997 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Inhibitors of both nuclear factor-κB and activator protein-1 activation block the neoplastic transformation response. / Li, Jian-Jian; Westergaard, Chandra; Ghosh, Paritosh; Colburn, Nancy H.
In: Cancer Research, Vol. 57, No. 16, 15.08.1997, p. 3569-3576.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inhibitors of both nuclear factor-κB and activator protein-1 activation block the neoplastic transformation response
AU - Li, Jian-Jian
AU - Westergaard, Chandra
AU - Ghosh, Paritosh
AU - Colburn, Nancy H.
PY - 1997/8/15
Y1 - 1997/8/15
N2 - Cross-coupling of active protein-1 tAP-1) and nuclear factor (NF)-κB has been reported. In the present study, we investigated the possibility that both of these two transcription factors might contribute to the process of tumor promoter-induced transformation. To establish a stable reporter cell system, two reporter genes were stably transfected into a JB6 mouse tumor promotion-sensitive (P+) cell line: a luciferase reporter controlled by a collagenase AP-1 sequence and a chloramphenicol acetyltransferase reporter controlled by an interleukin 6 NF-κB sequence. This double-reporter cell line maintained the phenotype of tumor promotion sensitivity and was able to report basal or induced AP-1 and NF-κB transactivation. The cytokine tumor promoter tumor necrosis factor (TNF)-α transactivated NF-κB and AP-1 for both DNA binding and transcriptional activity, Pyrrolidine dithiocarbamate, an antioxidant that acts as an NF-κB inhibitor, efficiently inhibited 12-O- tetradecanoylphorbol-13-acetate (TPA) or TNF-α induced NF-κB as well as AP- 1 transactivation and cell transformation, suggesting dependency of transformation on both transcription factors. The AP-1 transrepressing- retinoid SR11302 transrepressed AP-1 and cell transformation when these were TPA induced but not when TNF-α induced, indicating different signaling pathways for TNF-α and TPA. Supershift electrophoresis mobility shift assay revealed that Jun B and c-Jun were absent from the AP-1/DNA complex following TNF-α but present following TPA treatment. Together, these results suggest that both AP-1 and NF-κB activation may be required for transformation whether induced by TPA or by TNF, and the differential sensitivity of TPA and TNF-α-induced transformation to inhibition by a retinoid might be explained by differences in the composition of the DNA-bound AP-1 complexes.
AB - Cross-coupling of active protein-1 tAP-1) and nuclear factor (NF)-κB has been reported. In the present study, we investigated the possibility that both of these two transcription factors might contribute to the process of tumor promoter-induced transformation. To establish a stable reporter cell system, two reporter genes were stably transfected into a JB6 mouse tumor promotion-sensitive (P+) cell line: a luciferase reporter controlled by a collagenase AP-1 sequence and a chloramphenicol acetyltransferase reporter controlled by an interleukin 6 NF-κB sequence. This double-reporter cell line maintained the phenotype of tumor promotion sensitivity and was able to report basal or induced AP-1 and NF-κB transactivation. The cytokine tumor promoter tumor necrosis factor (TNF)-α transactivated NF-κB and AP-1 for both DNA binding and transcriptional activity, Pyrrolidine dithiocarbamate, an antioxidant that acts as an NF-κB inhibitor, efficiently inhibited 12-O- tetradecanoylphorbol-13-acetate (TPA) or TNF-α induced NF-κB as well as AP- 1 transactivation and cell transformation, suggesting dependency of transformation on both transcription factors. The AP-1 transrepressing- retinoid SR11302 transrepressed AP-1 and cell transformation when these were TPA induced but not when TNF-α induced, indicating different signaling pathways for TNF-α and TPA. Supershift electrophoresis mobility shift assay revealed that Jun B and c-Jun were absent from the AP-1/DNA complex following TNF-α but present following TPA treatment. Together, these results suggest that both AP-1 and NF-κB activation may be required for transformation whether induced by TPA or by TNF, and the differential sensitivity of TPA and TNF-α-induced transformation to inhibition by a retinoid might be explained by differences in the composition of the DNA-bound AP-1 complexes.
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UR - http://www.scopus.com/inward/citedby.url?scp=0030800330&partnerID=8YFLogxK
M3 - Article
C2 - 9270030
AN - SCOPUS:0030800330
VL - 57
SP - 3569
EP - 3576
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 16
ER -