Taken together, we demonstrated three two-locus pairs of polymorphisms with synergistic effect out of three genes in RAAS and found significant haplotype-phenotype interaction. Functional studies to confirm or refute these findings are warranted.
In contrast to conventional cyclin-dependent kinases that are important for mitotic cell division, cyclin-dependent kinase 5 (CDK5) is predominantly activated in post-mitotic cells and is involved in various cellular events. The kinase activity of CDK5 is tightly regulated by specific activators including p35, p39, and cyclin I (CCNI). Here we show that cyclin I-like (CCNI2), a homolog of CCNI, interacts with CDK5 and activates the kinase activity of CDK5. Different from CCNI, which colocalizes with CDK5 in the nuclei in transfected cells, CCNI2 mainly retains CDK5 in the cytoplasm as well as on the cell membrane. Furthermore, although the expression level of CCNI2 mRNA and CCNI2 protein do not change significantly during cell cycle, depletion of CCNI2 with siRNA affects cell cycle progression as well as cell proliferation. In conclusion, our data strongly suggest that CCNI2 is a novel CDK5 activator and is involved in cell cycle regulation.
Angulin proteins are a group of evolutionally conserved type I transmembrane proteins that contain an extracellular Ig-like domain. In mammals, three angulin proteins have been identified, namely immunoglobulin-like domain containing receptor 1 (ILDR1), immunoglobulin-like domain containing receptor 2 (ILDR2), and lipolysis-stimulated lipoprotein receptor (LSR). All three proteins have been shown to localize at tight junctions (TJs) and are important for TJ formation. Mutations in ILDR1 gene have been shown to cause non-syndromic hearing loss (NSHL). In the present work, we show that ILDR1 binds to splicing factors TRA2A, TRA2B, and SRSF1, and translocates into the nuclei when the splicing factors are present. Moreover, ILDR1 affects alternative splicing of Tubulin delta 1 (TUBD1), IQ motif containing B1 (IQCB1), and Protocadherin 19 (Pcdh19). Further investigation show that ILDR2, but not LSR, also binds to the splicing factors and regulates alternative splicing. When endogenous ILDR1 and ILDR2 expression is knockdown with siRNAs in cultured cells, alternative splicing of TUBD1 and IQCB1 is affected. In conclusion, we show here that angulin proteins ILDR1 and ILDR2 are involved in alternative pre-mRNA splicing via binding to splicing factors TRA2A, TRA2B, or SRSF1.
Neovascularization drives tumor development, and angiogenic factors are important neovascularization initiators. We recently identified the secreted angiogenic factor CNPY2, but its involvement in cancer has not been explored. Herein, we investigate CNPY2's role in human colorectal cancer (CRC) development. Tumor samples were obtained from CRC patients undergoing surgery. Canopy 2 (CNPY2) expression was analyzed in tumor and adjacent normal tissue. Stable lines of human HCT116 cells expressing CNPY2 shRNA or control shRNA were established. To determine CNPY2's effects on tumor xenografts in vivo, human CNPY2 shRNA HCT116 cells and controls were injected into nude mice, separately. Cellular apoptosis, growth, and angiogenesis in the xenografts were evaluated. CNPY2 expression was significantly higher in CRC tissues. CNPY2 knockdown in HCT116 cells inhibited growth and migration and promoted apoptosis. In xenografts, CNPY2 knockdown prevented tumor growth and angiogenesis and promoted apoptosis. Knockdown of CNPY2 in the HCT116 CRC cell line reversibly increased p53 activity. The p53 activation increased cyclin-dependent kinase inhibitor p21 and decreased cyclin-dependent kinase 2, thereby inhibiting tumor cell growth, inducing cell apoptosis, and reducing angiogenesis both in vitro and in vivo. CNPY2 may play a critical role in CRC development by enhancing cell proliferation, migration, and angiogenesis and by inhibiting apoptosis through negative regulation of the p53 pathway. Therefore, CNPY2 may represent a novel CRC therapeutic target and prognostic indicator.
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