The small leucine-rich repeat proteoglycan (SLRPs) family of proteins currently consists of five classes, based on their structural composition and chromosomal location. As biologically active components of the extracellular matrix (ECM), SLRPs were known to bind to various collagens, having a role in regulating fibril assembly, organization and degradation. More recently, as a function of their diverse proteins cores and glycosaminoglycan side chains, SLRPs have been shown to be able to bind various cell surface receptors, growth factors, cytokines and other ECM components resulting in the ability to influence various cellular functions. Their involvement in several signaling pathways such as Wnt, transforming growth factor-b and epidermal growth factor receptor also highlights their role as matricellular proteins. SLRP family members are expressed during neural development and in adult neural tissues, including ocular tissues. This review focuses on describing SLRP family members involvement in neural development with a brief summary of their role in non-neural ocular tissues and in response to neural injury.
These findings improve our understanding of the mechanism of cell death in Prominin-1-related disease and provide evidence that fenretinide may be worth studying in human disease.
Osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) are secreted extracellular matrix proteins belonging to the small leucine-rich proteoglycans family. We found that OMD and PRELP were specifically expressed in umbrella cells in bladder epithelia, and their expression levels were dramatically downregulated in all bladder cancers from very early stages and various epithelial cancers. Our in vitro studies including gene expression profiling using bladder cancer cell lines revealed that OMD or PRELP application suppressed the cancer progression by inhibiting TGF-β and EGF pathways, which reversed epithelial–mesenchymal transition (EMT), activated cell–cell adhesion, and inhibited various oncogenic pathways. Furthermore, the overexpression of OMD in bladder cancer cells strongly inhibited the anchorage-independent growth and tumorigenicity in mouse xenograft studies. On the other hand, we found that in the bladder epithelia, the knockout mice of OMD and/or PRELP gene caused partial EMT and a loss of tight junctions of the umbrella cells and resulted in formation of a bladder carcinoma in situ-like structure by spontaneous breakdowns of the umbrella cell layer. Furthermore, the ontological analysis of the expression profiling of an OMD knockout mouse bladder demonstrated very high similarity with those obtained from human bladder cancers. Our data indicate that OMD and PRELP are endogenous inhibitors of cancer initiation and progression by controlling EMT. OMD and/or PRELP may have potential for the treatment of bladder cancer.
In response to oncogenic signals, Alternative Splicing (AS) regulators such as SR and hnRNP proteins show altered expression levels, subnuclear distribution and/or posttranslational modification status, but the link between signals and these changes remains unknown. Here, we report that a cytosolic scaffold protein, IQGAP1, performs this task in response to heat-induced signals. We show that in gastric cancer cells, a nuclear pool of IQGAP1 acts as a tethering module for a group of spliceosome components, including hnRNPM, a splicing factor critical for the response of the spliceosome to heat-shock.IQGAP1 controls hnRNPM's sumoylation, subnuclear localization and the relevant response of the AS machinery to heat-induced stress. Genome-wide analyses reveal that IQGAP1 and hnRNPM co-regulate the AS of a cell cycle-related RNA regulon in gastric cancer cells, thus favouring the accelerated proliferation phenotype of gastric cancer cells. Overall, we reveal a missing link between stress signals and AS regulation. knockout generation, splicing assays, microscopy techniques and quantitation, immunostaining) are described in the Supplementary Material and Methods section. Cell culturesThe human STAD cell lines AGS, KATOIII, MKN45 and NUGC4 were used. When indicated, cells were treated with the sumoylation inhibitor III 2-D08 (Millipore, Cat# 505156) at 100 μM for 12 h. Mass spectrometry and Proteomics analysisAnti-IQGAP1 immunoprecipitation samples were processed in collaboration with the Core Proteomics Facility at EMBL Heidelberg. See Supplementary Materials and Methods. RNA-seq analysisAS was analysed by using VAST-TOOLS v2.2.2 (29) and expressed as changes in percentspliced-in values (∆PSI). To generate RNA maps, we used the rna_maps function (30), using sliding windows of 15 nucleotides as described in Supplementary Materials and Methods. Quantification and Statistical AnalysisData were analysed using GraphPad Prism 7 software (GraphPad Software). Student's t test (comparisons between two groups), one-way ANOVA were used as indicated in the legends. p <0.05 was considered statistically significant. ACCESSION NUMBERSThe mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE 69 partner repository with the dataset identifier PXD017842.RNA-seq data have been deposited in GEO: GSE146283.
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