1. Tranilast, first developed as an anti-allergic drug, has been reported to inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis and vasopermeability. To further clarify the inhibitory mechanism, we investigated the effects of tranilast on VEGF binding and subsequent intracellular signalling pathway linked to angiogenic activities and gene expression of bovine retinal microcapillary endothelial cells. 2. Tranilast significantly (P<0.01) inhibited VEGF, basic fibroblast growth factor (bFGF), and hypoxia conditioned media-induced BREC proliferation in a dose dependent manner with IC50's of 22, 82 and 10 microM, respectively. 3. VEGF-induced migration was also inhibited by tranilast in a dose dependent manner, with IC50 of 18 microM, and complete inhibition was observed at 300 microM (P<0.01). Tranilast suppressed VEGF-induced tube formation in a dose dependent manner with maximum (46%) inhibition observed at 300 microM (P<0.05). 4. Tranilast inhibited phorbol myristate acetate (PMA)-dependent stimulation of [3H]-thymidine incorporation and VEGF- and PMA-induced gene expression of integrin alpha v and c-fos in BREC. 5. Tranilast suppressed VEGF- and PMA-stimulated PKC activity in BREC. 6. Tranilast did not affect VEGF binding or VEGF-induced phosphorylation of tyrosine residues of VEGF receptor- and phospholipase Cgamma and their associated proteins. 7. These data suggest that tranilast might prove an effective inhibitor to prevent retinal neovascularization in ischaemic retinal diseases, and that its inhibitory effect might be through suppression of PKC-dependent signal transduction in BREC.

DBC1/KIAA1967 (deleted in breast cancer 1) is a putative tumour-suppressor gene cloned from a heterozygously deleted region in breast cancer specimens. Caspase-dependent processing of DBC1 promotes apoptosis, and depletion of endogenous DBC1 negatively regulates p53-dependent apoptosis through its specific inhibition of SIRT1. Hereditary breast and ovarian cancer susceptibility gene product BRCA1, by binding to the promoter region of SIRT1, is a positive regulator of SIRT1 expression.

The TFII-I is a multifunctional transcriptional factor known to bind specifically to several DNA sequence elements and to mediate growth factor signalling. A microdeletion at the chromosomal location 7q11.23 encoding TFII-I and the related family of transcription factors may result in the onset of Williams-Beuren syndrome, an autosomal dominant genetic disorder characterised by a unique cognitive profile, diabetes, hypertension, anxiety, and craniofacial defects. Hereditary breast and ovarian cancer susceptibility gene product BRCA1 has been shown to serve as a positive regulator of SIRT1 expression by binding to the promoter region of SIRT1, but cross talk between BRCA1 and TFII-I has not been investigated to date.

The Ral GTPase is activated by RalGDS, which is one of the effector proteins for Ras. Previous studies have suggested that Ral might function to regulate the cytoskeleton; however, its in vivo function is unknown. We have identified a Drosophila homologue of Ral that is widely expressed during embryogenesis and imaginal disc development. Two mutant Drosophila Ral (DRal) proteins, DRal(G20V) and DRal(S25N), were generated and analyzed for nucleotide binding and GTPase activity. The biochemical analyses demonstrated that DRal(G20V) and DRal(S25N) act as constitutively active and dominant negative mutants, respectively. Overexpression of the wild-type DRal did not cause any visible phenotype, whereas DRal(G20V) and DRal(S25N) mutants caused defects in the development of various tissues including the cuticular surface, which is covered by parallel arrays of polarized structures such as hairs and sensory bristles. The dominant negative DRal protein caused defects in the development of hairs and bristles. These phenotypes were genetically suppressed by loss of function mutations of hemipterous and basket, encoding Drosophila Jun NH(2)-terminal kinase kinase (JNKK) and Jun NH(2)-terminal kinase (JNK), respectively. Expression of the constitutively active DRal protein caused defects in the process of dorsal closure during embryogenesis and inhibited the phosphorylation of JNK in cultured S2 cells. These results indicate that DRal regulates developmental cell shape changes through the JNK pathway.