Alternative splicing of fibroblast growth factor receptor 2 (FGFR2) transcripts occurs in a cell-type-specific manner leading to the mutually exclusive use of exon IIIb in epithelia or exon IIIc in mesenchyme. Epithelial cell-specific exon choice is dependent on (U)GCAUG elements, which have been shown to bind Fox protein family members. In this paper we show that FGFR2 exon choice is regulated by (U)GCAUG elements and Fox protein family members. Fox-2 isoforms are differentially expressed in IIIb ؉ cells in comparison to IIIc ؉ cells, and expression of Fox-1 or Fox-2 in the latter led to a striking alteration in FGFR2 splice choice from IIIc to IIIb. This switch was absolutely dependent on the (U)GCAUG elements present in the FGFR2 pre-mRNA and required critical residues in the C-terminal region of Fox-2. Interestingly, Fox-2 expression led to skipping of exon 6 among endogenous Fox-2 transcripts and formation of an inactive Fox-2 isoform, which suggests that Fox-2 can regulate its own activity. Moreover, the repression of exon IIIc in IIIb There are four well-characterized fibroblast growth factor receptors (FGFRs), which contain a single transmembrane domain, an intracellular tyrosine kinase domain, and an extracellular FGF binding domain composed of two or three immunoglobulin (Ig)-like domains. The transcripts encoding three FGFRs (FGFR1, -2, and -3) are alternatively spliced to produce isoforms that contain one of two different Ig-III domains. Alternative splicing of FGFR2 transcripts results in the production of two receptors that differ in the carboxy-terminal half of the Ig-III domain. This hemidomain is determined by the tissue-specific inclusion of either exon IIIb or exon IIIc, which ultimately controls ligand binding specificity (7,14,27,52). FGFR2(IIIb) primarily binds FGF10 and FGF7 and is the isoform of choice in epithelial cells, whereas FGFR2(IIIc) binds FGF2 and is exclusively expressed in cells of mesenchymal origin (36, 49). FGF/FGFR2 signaling governs epithelialmesenchymal interactions that are required for organogenesis in mouse embryos (3, 15, 16); therefore, it is critical for normal development to maintain the proper cell-type-specific expression of each receptor isoform. Mutations that alter the ligand binding specificity of FGFR2(IIIc) or those that lead to the inappropriate expression of exon IIIb in mesenchyme have been linked to developmental disorders in humans (3,16,35,54). The importance of FGFR2 isoform choice is underscored by studies demonstrating a switch from FGFR2(IIIb) to FGFR2(IIIc) during the progression of prostate carcinomas (4, 49), where the loss of FGFR2(IIIb) appears to be required for this progression (51).The regulation of FGFR2 alternative splicing depends on a complex interplay between cis-acting elements in the FGFR2 pre-mRNA and trans-acting factors, with some of the transacting factors appearing to be cell type specific. To study this regulation, we have employed two cell lines derived from Dunning rat prostate tumors. The DT3 cell line is a well-differenti...

A new cytotoxic cytochalasan-based alkaloid named chaetoglobosin U (1), along with four known analogues, chaetoglobosins C (2), F (3), and E (5) and penochalasin A (4), has been characterized from the EtOAc extract of a solid culture of Chaetomium globosum IFB-E019, an endophytic fungus residing inside the stem of healthy Imperata cylindrica. The structure of chaetoglobosin U was determined through correlative analyses of its UV, IR, CD, MS, and 1D ((1)H and(13)C NMR and DEPT) and 2D NMR (COSY, NOESY, HMQC, and HMBC) data. Chaetoglobosin U (1) exhibited cytotoxic activity against the human nasopharyngeal epidermoid tumor KB cell line with an IC(50) value of 16.0 microM, comparable to that (14.0 microM) of 5-fluorouracil co-assayed as a positive reference. The known analogues 2-5 were moderately active to the cell line, with IC(50) values of 34.0, 52.0, 48.0, and 40.0 microM, respectively.

A new diphenyl ether, named neoplaether, together with five known compounds monomethylsulochrin, physcion, helvolic acid, ergosterol and ergosterol peroxide, was isolated from the culture of Neoplaconema napellum IFB-E016, an endophytic fungus residing in the healthy leaves of Hopea hainanensis. The structure of neoplaether was elucidated by a correlative interpretation of its infrared spectrometry, mass spectroscopy and nuclear magnetic resonance spectra, and confirmed by its single-crystal X-ray diffraction analysis. Neoplaether exhibited significant cytotoxic activity against the human nasopharyngeal epidermoid tumor KB cell line, with an IC(50) value of 13.0 microg mL(-1), comparable to that of 5-fluorouracil (2.5 microg mL(-1)) co-assayed as a positive reference. In addition, it showed antifungal activity against Candida albicans, with a minimal inhibitory concentration value of 6.2 microg mL(-1) (amphotericin as a positive control had a value of 1.5 microg mL(-1)).