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 dierential 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 7152 bp promoter, which contains two functional TRE sites. Even though the basal level AP-1 protein DNA binding pattern is dierent between normal and malignant cells, PMA signi®cantly enhances Jun and Fos binding to the consensus TRE site in both cell types. Intriguingly, the composition of AP-1 protein binding to the 7152 to 786 bp SPRR1B promoter is quite dierent. In untreated cells, SPRR1B promoter is predominantly occupied by JunD and Fra2. PMA signi®cantly 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 signi®cantly 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 dierential activation of AP-1 proteins, especially Fra1 and Fra2, might contribute to the dysregulation of terminal dierentiation marker, SPRR1B, expression in various BE cells. Oncogene (2001) 20, 634 ± 644.

Gene expression-based, individualized outcome prediction for surgically treated lung cancer patients

“…The MYC oncogene, frequently overexpressed with or without amplification in lung cancers, is associated with a poor prognosis (Johnson et al, 1987), as is SERPINE1. (Robert et al, 1999) FOSL1 has been shown to play a role as a predominant component of the AP-1 complex in ras-induced transformation (Mechta et al, 1997), and it also mediates induction of SPRR1B in response to epithelial injury caused by a variety of carcinogens (Patterson et al, 2001;Vuong et al, 2002). Both COPB and ARCN1 constitute COPI-coated vesicles and are involved in the transport of G protein-coupled receptors, while the binding of Ras-related GTP-binding protein Cdc42 to another COPI subunit, COPG, has been shown to be important for transmitting transforming signals (Wu et al, 2000).…”

Mitogen regulated induction of FRA-1 proto-oncogene is controlled by the transcription factors binding to both serum and TPA response elements

“…For example, various toxicants and known carcinogens, such as tobacco smoke, silica and asbestos, persistently activate fra-1 but not fra-2 expression in lung cells (Reddy and Mossman, 2002). We have shown that FRA-1 upregulates the expression of genes associated with airway squamous cell metaplasia (Patterson et al, 2001) and that of matrix metalloproteinase-9, which is implicated in toxin-induced respiratory pathogenesis (Parks and Shapiro, 2001). Since an upregulation of FRA-1, rather than a mutational activation, contributes to the growth and proliferation of human tumors, it is important to understand its regulation.…”

A Phosphatidylinositol 3-Kinase-regulated Akt-Independent Signaling Promotes Cigarette Smoke-induced FRA-1 Expression

“…For example, FRA-1 is required for asbestos-induced mesothelial cell transformation (17). It up-regulates the expression of genes coding for airway squamous cell metaplastic marker (18), matrix metalloproteinase-9 (19), and CD44 and c-met proto-oncogene (20), which are implicated in toxin-induced respiratory pathogenesis. FRA-1 controls cell motility, invasion, and maintenance and progression of the transformed state in several cell types (for reviews, see Refs.…”