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The AP-1 transcription factor regulates breast cancer cell growth via cyclins and E2F factors

Oncogene volume 27, pages 366–377 (2008)Cite this article

Abstract

The activating protein-1 (AP-1) transcription factor transduces growth signals through signal transduction pathways to the nucleus, leading to the expression of genes involved in growth and malignant transformation in many cell types. We have previously shown that overexpression of a dominant negative form of the cJun proto-oncogene, a cJun dominant negative mutant (Tam67), blocks AP-1 transcriptional activity, induces a G1 cell cycle block and inhibits breast cancer cell growth in vitro and in vivo. We found that AP-1 blockade by Tam67 in MCF-7 breast cancer cells downregulates cyclin D1 transcriptional activity by at least two mechanisms: by suppressing transcription at the known AP-1 binding site (−934/−928) and by suppressing growth factor-induced expression through suppressing E2F activation at the E2F-responsive site (−726/−719). AP-1 blockade also led to reduced expression of E2F1 and E2F2, but not E2F4, at the mRNA and protein levels. Chromatin immunoprecipitation and supershift assays demonstrated that AP-1 blockade caused decreased binding of E2F1 protein to the E2F site in the cyclin D1 promoter. We also found that Tam67 suppressed the expression of the E2F1 dimerizing partner, DP1 and E2F-upregulated cell cycle genes (cyclins E, A, B and D3) and enhanced the expression of E2F-downregulated cell cycle genes (cyclins G2 and I). Reduced expression of other E2F-regulated genes was also seen with AP-1 blockade and E2F suppression. Thus, the AP-1 factor regulates the expression of cyclin D and E2F (the latter in turn regulates E2F-downstream genes), leading to cell cycle progression and breast cancer cell proliferation.

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Abbreviations

AP-1:

activating protein-1

ChIP:

chromatin immunoprecipitation

Dox:

doxycycline

EMSA:

electrophoretic mobility shift assay

ER:

estrogen receptor

NE:

nuclear extract

RPA:

RNase protection assay

Tam67:

a cJun dominant-negative mutant

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Acknowledgements

We thank Shirley Pennington for her assistance in preparing this manuscript. This work was supported by a pilot grant from the Dan L Duncan Cancer Center at Baylor College of Medicine.

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Authors and Affiliations

  1. Departments of Medicine and Molecular and Cellular Biology, Breast Center, Baylor College of Medicine, Houston, TX, USA

    Q Shen, I P Uray, Y Li, T I Krisko, T E Strecker, H-T Kim & P H Brown

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  1. Q Shen
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  2. I P Uray
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  3. Y Li
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  7. P H Brown
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Correspondence to P H Brown.

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Shen, Q., Uray, I., Li, Y. et al. The AP-1 transcription factor regulates breast cancer cell growth via cyclins and E2F factors. Oncogene 27, 366–377 (2008). https://doi.org/10.1038/sj.onc.1210643

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