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

Tricia Patterson, Hue Vuong, Yuang Shuang Liaw, Reen Wu, Dhananjaya V. Kalvakolanu, Sekhar P M Reddy

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

The overexpression of SPRRIB 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 Fral 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 fra1, 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.

Original languageEnglish (US)
Pages (from-to)634-644
Number of pages11
JournalOncogene
Volume20
Issue number5
DOIs
StatePublished - Feb 1 2001

Keywords

  • AP-1 proteins
  • Bronchial epithelial cells
  • SPRR1
  • Squamous cell differentiation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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