title: Mechanism of repression of squamous differentiation marker, SPRR1B, in malignant bronchial epithelial cells: role of critical TRE-sites and its transacting factors.
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.
authors: The Johns Hopkins University School of Public Health, Department of Environmental Health Sciences, 615 North Wolfe Street, Baltimore, MD 21205, USA.
authors: T
authors: T
authors: Patterson
authors: H
authors: H
authors: Vuong
authors: Y S
authors: YS
authors: Liaw
authors: R
authors: R
authors: Wu
authors: D V
authors: DV
authors: Kalvakolanu
authors: S P
authors: SP
authors: Reddy
mesh_terms: D000818:Animals; D001483:Base Sequence; D001980:Bronchi / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D055233:Cornified Envelope Proline-Rich Proteins; D018983:DNA Footprinting; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology; D051921:Fos-Related Antigen-2; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008253:Macaca mulatta; D008565:Membrane Proteins; D020409:Molecular Motor Proteins; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D020218:Response Elements / Q000187:drug effects / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014132:Trachea / Q000378:metabolism / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000099169:Fos-Related Antigen 1
chemical_list: D055233:Cornified Envelope Proline-Rich Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D051921:Fos-Related Antigen-2; D008565:Membrane Proteins; D020409:Molecular Motor Proteins; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos; D013755:Tetradecanoylphorbol Acetate; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000099169:Fos-Related Antigen 1; C497872:FOSL2 protein, human; C524533:SPRR1B protein, human