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Mechanism of repression of squamous differentiation marker, SPRR1B, in malignant bronchial epithelial cells: role of critical TRE-sites and its transacting factors

Oncogene volume 20, pages 634–644 (2001)Cite this article

Abstract

The overexpression of SPRR1B in bronchial epithelium is a marker for early metaplastic changes and the loss of its expression is associated with an irreversible malignant transformation. In the present study, we have used a model system consisting of normal and malignant bronchial epithelial (BE) cells to elucidate the differential transcriptional control of SPRR1B. SPRR1B expression is either detectable or PMA (phorbol 13-myristate 12-acetate) -inducible in several malignant BE cells including squamous, adeno, small and large cell carcinomas. Loss of SPRR1B expression is correlated well with the lack of strong in vivo protein-DNA interactions at the −152 bp promoter, which contains two functional TRE sites. Even though the basal level AP-1 protein DNA binding pattern is different between normal and malignant cells, PMA significantly enhances Jun and Fos binding to the consensus TRE site in both cell types. Intriguingly, the composition of AP-1 protein binding to the −152 to −86 bp SPRR1B promoter is quite different. In untreated cells, SPRR1B promoter is predominantly occupied by JunD and Fra2. PMA significantly induced binding of JunB and Fra1 in normal cells, while JunB and Fra2 bound to TREs in the malignant cells. Overexpression of fra1 in malignant cells significantly enhanced SPRR1B promoter activity. In contrast, overexpression of fra2, but not fra1, strongly reduced both basal and PMA-inducible promoter activities in normal cells. Together, these results indicate that either temporal expression and/or differential activation of AP-1 proteins, especially Fra1 and Fra2, might contribute to the dysregulation of terminal differentiation marker, SPRR1B, expression in various BE cells.

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Acknowledgements

The authors would like to thank Drs M Birrer, E Tulchinsky and D Cohen for providing us with the pCMV expression vectors of c-Jun, fra1 and fra2, respectively. We also thank Dr R Isseroff for providing us with primary cultured human epidermal keratinocytes. This work was supported in parts by grants from NIH HL-58122 (to SPM Reddy), ES-06230 (to R Wu), CA-71401 and CA-78282 (to DV Kalvakolanu). We would like to acknowledge the Johns Hopkins Urban Environmental Center (supported by grant from NIEHS ES03819) for use of its core facilities.

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Author notes

  1. Yuang-Shuang Liaw

    Present address: Department of Internal Medicine, National Taiwan University Hospital, Taiwan

  2. Tricia Patterson, Hue Vuong and Yuang-Shuang Liaw: T Patterson, H Vuong and Y-S Liaw contributed equally to this paper.

Authors and Affiliations

  1. Department of Environmental Health Sciences, The Johns Hopkins University School of Public Health, Baltimore, MD 21205, Maryland, USA

    Tricia Patterson, Hue Vuong & Sekhar PM Reddy

  2. School of Medicine, University of California at Davis, CA 95616, California, USA

    Yuang-Shuang Liaw & Reen Wu

  3. Greenbaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, Maryland, USA

    Dhananjaya V Kalvakolanu

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Patterson, T., Vuong, H., Liaw, YS. et al. Mechanism of repression of squamous differentiation marker, SPRR1B, in malignant bronchial epithelial cells: role of critical TRE-sites and its transacting factors. Oncogene 20, 634–644 (2001). https://doi.org/10.1038/sj.onc.1204134

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