Members of the transforming growth factor beta (TGF-β) superfamily are multifunctional cytokines that regulate several cellular processes, including cell cycle arrest, differentiation, morphogenesis, and apoptosis. TGF-β promotes extracellular matrix production and morphological change. Morphogenetic responses to TGF-β include cell migration and epithelial–mesenchymal transition (EMT), which are critical during embryogenesis, development of fibrotic diseases, and the spreading of advanced carcinomas. The purpose of this study was to clarify how TGF-β regulates the fate of retinal pigment epithelial (RPE) cells. TGF-β1 promoted cell cycle progression and phosphorylation of retinoblastoma protein (Rb) in ARPE-19 cells. TGF-β1 induced survivin expression, which in turn stabilized tubulin and Aurora B. RT-PCR and western blot analysis revealed that survivin expression increased in ARPE-19 cells following TGF-β1 treatment. When survivin was depleted, TGF-β1 induced cell cycle arrest and apoptosis and also reduced Rb phosphorylation. In conclusion, the present study shows that induction of EMT in human RPE cells upregulates survivin, leading to survivin-dependent inhibition of cell cycle arrest and apoptosis. Whether cells undergo EMT or apoptosis in response to TGF-β1 is dependent on their cell cycle state, and TGF-β1 regulates the cell cycle via survivin.

Many of the signaling responses induced by transforming growth factor-b (TGF-b) are mediated by Smad proteins, but there is evidence that it can also signal independently of Smads. Here, we provide evidence that multiple signal pathways induced by TGF-b1-including Src family tyrosine kinases (SFKs), generation of reactive oxygen species (ROS), de novo protein synthesis and E-cadherindependent cell-cell interactions-transactivate the epidermal growth factor receptor (EGFR), which in turn regulates expression of c-Fos and c-Jun. Immunoprecipitation and immunofluorescence staining showed that EGFR was phosphorylated on tyrosine in response to TGF-b1. EGFR transactivation required the activation of SFKs and the production of ROS via NADPH oxidase, but was not dependent on metalloproteases or the release of EGF-like ligands. In addition, the production of ROS was dependent on signaling by specific SFKs as well as de novo protein synthesis. Stable transfection of E-cadherin into MDA-MB-231 cells as well as E-cadherin-blocking assays revealed that E-cadherin-mediated cell-cell interactions were also essential for EGFR transactivation. Finally, EGFR transactivation was involved in the expression of c-Fos and c-Jun via the extracellular signal-regulated kinase signaling cascade. Taken together our data suggest that ligand release-independent transactivation of EGFR may diversify early TGF-b signaling and represent a novel pathway leading to TGF-b-mediated gene expression.

We analyzed the incidence and risk factors for ocular GVHD in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Korea. In this retrospective, noncomparative, observational study, 635 subjects were included who had at least 2 years of follow-up ophthalmological examinations after allo-HSCT from 2009 to 2012 at Seoul St Mary's Hospital, Seoul, Korea. The mean duration between allo-HSCT and onset of ocular GVHD was 225.5 ± 194.3 days. The adjusted incidence for acute ocular GVHD was 1.33% and that for chronic GVHD was 33.33%. In the multivariate analysis, preexisting diabetes mellitus (odds ratio (OR): 4.22, 95% confidence interval (CI): 1.66-10.72), repeated allo-HSCT (OR: 29.10, 95% CI: 1.02-8.28) and the number of organs that chronically developed GVHD by stage I (OR: 14.63, 95% CI: 9.81-21.84) increased risk of ocular GVHD. Careful monitoring of ocular GVHD is needed in patients with chronic GVHD in multiple organs and preexisting diabetes.