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CRE DNA binding proteins bind to the AP-1 target sequence and suppress AP-1 transcriptional activity in mouse keratinocytes

Oncogene volume 18, pages 1569–1579 (1999)Cite this article

Abstract

Previously, we have shown that nuclear extracts from cultured mouse keratinocytes induced to differentiate by increasing the levels of extra-cellular calcium contain Fra-1, Fra-2, Jun B, Jun D and c-Jun proteins that bind to the AP-1 DNA binding sequence. Despite this DNA binding activity, AP-1 reporter activity was suppressed in these cells. Here, we have detected the CREB family proteins CREB and CREMα as additional participants in the AP-1 DNA binding complex in differentiating keratinocytes. AP-1 and CRE DNA binding activity correlated with the induction of CREB, CREMα and ATF-1 and CREB phosphorylation at ser133 (ser133 phospho-CREB) in the transition from basal to differentiating keratinocytes, but the activity of a CRE reporter remained unchanged. In contrast, the CRE reporter was activated in the presence of the dominant-negative (DN) CREB mutants, KCREB and A-CREB, proteins that dimerize with CREB family members and block their ability to bind to DNA. The increase in CRE reporter activity in the presence of these mutants suggests that CRE-mediated transcriptional activity is suppressed in keratinocytes through protein-protein interactions involving a factor that dimerizes with the CREB leucine zipper. In experiments where the A-CREB mutant was co-transfected with an AP-1 reporter construct, transcriptional activity was also increased indicating that a CREB family member binds AP-1 sites and represses AP-1 transcriptional activity as well. Exogenous expression of the transcriptional repressor CREMα down-regulated both CRE and AP-1 reporters in keratinocytes suggesting that this factor may contribute to the suppression of AP-1 transcriptional activity observed in differentiating keratinocytes.

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Acknowledgements

The authors thank Richard Goodman for the KCREB and CREMα expression vectors, Seong-Jin Kim for the TGFβ3 promoter constructs, Donna Cohen for the Fra-2 expression vector, and Robert Tarone for performing the statistical analysis.

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Authors and Affiliations

  1. Division of Basic Sciences, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, USA

    S E Rutberg, T L Adams, N Alexander & S H Yuspa

  2. Division of Basic Sciences, Laboratory of Biochemistry, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, USA

    M Olive & C Vinson

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  1. S E Rutberg
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  2. T L Adams
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Rutberg, S., Adams, T., Olive, M. et al. CRE DNA binding proteins bind to the AP-1 target sequence and suppress AP-1 transcriptional activity in mouse keratinocytes. Oncogene 18, 1569–1579 (1999). https://doi.org/10.1038/sj.onc.1202463

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