Human ABCC5 blocking peptide

ATP-binding cassette (ABC) transporters are evolutionarily conserved proteins that pump diverse substrates across membranes. Many are known to efflux signaling molecules and are extensively expressed during development. However, the role of transporters in moving extracellular signals that regulate embryogenesis is largely unexplored. Here, we show that a mesodermal ABCC (MRP) transporter is necessary for endodermal gut morphogenesis in sea urchin embryos. This transporter, Sp-ABCC5a (C5a), is expressed in pigment cells and their precursors, which are a subset of the non-skeletogenic mesoderm (NSM) cells. C5a expression depends on Delta/Notch signaling from skeletogenic mesoderm and is downstream of Gcm in the aboral NSM gene regulatory network. Long-term imaging of development reveals that C5a knockdown embryos gastrulate, but similar to 90% develop a prolapse of the hindgut by the late prism stage (similar to 8 h after C5a protein expression normally peaks). Since C5a orthologs efflux cyclic nucleotides, and cAMP-dependent protein kinase (Sp-CAPK/PKA) is expressed in pigment cells, we examined whether C5a could be involved in gastrulation through cAMP transport. Consistent with this hypothesis, membrane-permeable pCPT-cAMP rescues the prolapse phenotype in C5a knockdown embryos, and causes archenteron hyper-invagination in control embryos. In addition, the cAMP-producing enzyme soluble adenylyl cyclase (sAC) is expressed in pigment cells, and its inhibition impairs gastrulation. Together, our data support a model in which C5a transports sAC-derived cAMP from pigment cells to control late invagination of the hindgut. Little is known about the ancestral functions of ABCC5/MRP5 transporters, and this study reveals a novel role for these proteins in mesoderm-endoderm signaling during embryogenesis.

This study aimed to identify the association between lnc-LAMC2-1:1 polymorphism rs2147578 and the recurrence of ovary cancer, as well as to study the underlying mechanism of rs2147578 in ovary cancer. Real-time polymerase chain reaction, Western blot analysis, immunohistochemistry, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Logrank test, and Kaplan-Meier analysis were carried out to explore the role of rs2147578 in ovary cancer. No obvious difference was observed concerning all clinical characteristics among 90 patients genotyped as CC (N = 28), CG (N = 38), and GG (N = 24) in their rs2147578 polymorphism. In addition, the subjects carrying the CC genotype had longer recurrence-free survival time and showed a lower level of malignancy compared with those carrying CG and GG genotypes. Lnc-LAMC2-1:1 and miR-128 were lowly expressed in the CC group, while deleted in colorectal cancer (DCC) was highly expressed in the CC group. Furthermore, DCC was identified as a target gene of miR-128, and miR-128 mimics decreased the luciferase activity of cells cotransfected with wild-type DCC 3 '-untranslated region. Lnc-LAMC2:1-1 directly targeted and affected miR-128 expression, and the G allele in lnc-LAMC2-1:1 rs2147578 upregulated miR-128 expression. Transfection with a miR-128 precursor evidently downregulated the expression of lnc-LAMC2-1:1, miR-128, and DCC expression, but did not affect the expression of ABCC5 and body mass index. Finally, miR-128 precursor promoted cell proliferation and inhibited cell apoptosis. Compared with lnc-LAMC2-1:1 rs2147578C allele, the G allele increases the risk of ovarian cancer by reducing the binding between lnc-LAMC2-1:1 and miR-128-3p, which in turn further decreases the expression of DCC and inhibits cell apoptosis.