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Preferential primary-response gene expression in promotion-resistant versus promotion-sensitive JB6 cells
J L Cmarik1, H Herschman, N H Colburn
1Laboratory of Viral Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland 21702.
Abstract:
The 12-O-tetradecanoylphorbol-13-acetate (TPA)-inducible sequence (TIS) genes are a set of primary response genes induced in Swiss 3T3 cells by TPA. They include three transcription factors, a prostaglandin synthase, and three proteins of unknown function. To ascertain which, if any TIS genes might be involved in tumor promotion, we examined the expression of these genes in response to tumor promoters in transformation promotion-sensitive (P+) and -resistant (P-) JB6 murine epidermal cells, a model used to identify events relevant to promotion. A subset of TIS genes (TIS1, TIS10, and TIS21) was preferentially induced by TPA in P-cells. In addition, TIS1 and TIS21 mRNAs were preferentially induced in P-cells by epidermal growth factor, another transformation promoter that distinguishes P+ from P-cells. TIS1 and TIS21 protein levels were also greater in TPA-treated P-cells than P+ cells. Forskolin, a cAMP-elevating anti-promoter, increased TPA-induced levels of TIS1, TIS10, and TIS21 mRNAs in P+ cells, ruling in potential roles for these genes in modulating tumor promotion. The anti-promoters fluocinolone acetonide, retinoic acid, and superoxide dismutase did not enhance TPA-induced levels of TIS1 and TIS21 mRNAs in P+ cells, suggesting that these inhibitors may act on other promotion-relevant genes. TIS1 encodes a member of the steroid receptor superfamily. TIS1 encodes a protein of unknown function with strong sequence similarity to BTG1, a proposed "anti-proliferative gene" (Rouault JP, Rimokh R, Tessa C, et al., EMBO J 11:1663-1670, 1992). Preferential induction by multiple promoters of these TIS genes in P-cells and enhancement of their induction in P+ cells by the anti-promoter forskolin make TIS1 and TIS21 candidates for promotion suppressor genes.
Insights
Tumor promotion involves specific 12-O-tetradecanoylphorbol-13-acetate (TPA)-inducible sequence (TIS) genes. TIS1 and TIS21 are preferentially induced in promotion-resistant cells, suggesting they may act as tumor promotion suppressor genes.
Area of Science:
- Molecular biology
- Cancer research
- Cell signaling
Background:
- 12-O-tetradecanoylphorbol-13-acetate (TPA)-inducible sequence (TIS) genes are primary response genes.
- TIS genes include transcription factors, prostaglandin synthase, and proteins of unknown function.
- Understanding TIS gene involvement in tumor promotion is crucial for cancer research.
Purpose of the Study:
- To investigate the role of TIS genes in tumor promotion.
- To examine TIS gene expression in transformation promotion-sensitive (P+) and -resistant (P-) JB6 murine epidermal cells.
- To identify TIS genes relevant to tumor promotion mechanisms.
Main Methods:
- Analyzed TIS gene expression in response to tumor promoters (TPA, epidermal growth factor) in P+ and P- JB6 cells.
- Quantified TIS mRNA and protein levels.
- Assessed the effects of anti-promoters (forskolin, fluocinolone acetonide, retinoic acid, superoxide dismutase) on TIS gene induction.
Main Results:
- TIS1, TIS10, and TIS21 were preferentially induced by TPA in P- cells.
- TIS1 and TIS21 mRNAs and proteins were upregulated in P- cells compared to P+ cells.
- Forskolin enhanced TPA-induced TIS1, TIS10, and TIS21 mRNA levels in P+ cells.
Conclusions:
- TIS1 and TIS21 are preferentially induced by tumor promoters in promotion-resistant cells.
- TIS1 and TIS21 show potential roles in modulating tumor promotion.
- TIS1 and TIS21 are candidates for promotion suppressor genes.