Zinc-finger BED domain-containing 3 (Zbed3) is a novel secreted protein associated with insulin resistance in humans. Jia Y et al. (2014) Genome-wide association studies (GWAS) have shown that Zbed3 is associated with T2DM. To date, no report has demonstrated a relationship between Zbed3 and insulin resistance in humans, however. The purpose of this study was to determine whether the Zbed3 protein is secreted and identify any associations between Zbed3 and insulin resistance in cross-sectional and interventional studies. We found that Zbed3 protein was secreted in an in vitro secretion study. Plasma Zbed3 levels were determined in an ELISA and were compared with various parameters related to insulin resistance in subjects with NGT, IGT and nT2DM. EHC was performed in healthy subjects. Real-time PCR and Western blotting were used to assess the mRNA and protein expression of Zbed3. Zbed3 was detected in an analysis of in vitro secretion in both conditioned medium and lysates of HEK-293T cells transfected with an overexpressed vector. In a clinical study, there were significantly higher levels of circulating Zbed3 in IGT and nT2DM relative to NGT. Zbed3 levels were positively correlated with BMI, WHR, FAT%, blood pressure, FBG, TG, HbA1c, FIns and HOMA-IR and inversely correlated with HDL-C. Increasing levels of Zbed3 were independently associated with IGT and T2DM. Zbed3 mRNA and protein in muscle and fat were significantly elevated in both db/db mice and T2DM patients. Moreover, there was a concentration-dependent effect of glucose on Zbed3 release, whereas insulin exhibited an inhibitory effect on Zbed3 levels. Zbed3 suppressed insulin-induced IR and Akt phosphorylation. These results suggest that the Zbed3 protein may be a cytokine associated with insulin resistance in humans that is influenced by glucose and insulin levels.//////////////////Identification of zinc-finger BED domain-containing 3 (Zbed3) as a novel Axin-interacting protein that activates Wnt/beta-catenin signaling. Chen T et al. (2009) Axin, a key modulator of the Wnt/beta-catenin pathway, acts as a scaffold protein in phosphorylating and degrading cytoplasmic beta-catenin. Canonical Wnt proteins appear to stabilize beta-catenin by inducing the interaction of LRP5/6 with Axin. This interaction requires the phosphorylation of the Ser or Thr residues in the PPPP(S/T)PX(T/S) motifs at the intracellular domain of LRP5/6. In this work, we identified a novel Axin-interacting protein, zinc-finger BED domain-containing 3 (Zbed3), by yeast two-hybrid screening. The interaction was confirmed in co-immunoprecipitation experiment in mammalian cells and in vitro pulldown assays. Moreover, we found Zbed3 also contains a PPPPSPT motif, which is crucial to its binding to Axin. The Ser and Thr residues in the motif appear to be also phosphorylated by glycogen synthase kinase 3beta (GSK3beta) and the CKI family kinases, as GSK3beta and CKIepsilon could enhance the interaction of Zbed3 with Axin. Mutation of the Ser (SA) or Thr (TA) residue to Ala in the motif markedly impaired its ability to interact with Axin. Expressing Zbed3, but not these mutants, led to inhibition of GSK3beta-mediated beta-catenin phosphorylation, cytoplasmic beta-catenin accumulation, and activation of lymphoid enhancer binding factor-1-dependent reporter gene transcription. Furthermore, knockdown of Zbed3 with RNA interference attenuated Wnt-induced beta-catenin accumulation, lymphoid enhancer binding factor-1-dependent luciferase reporter activity, and the Wnt target gene expression. These results together indicate that Zbed3 is a novel Axin-binding protein that is involved in Wnt/beta-catenin signaling modulation.//////////////////
NCBI Summary:
This gene belongs to a class of genes that arose through hAT DNA transposition and that encode regulatory proteins. This gene is upregulated in lung cancer tissues, where the encoded protein causes an accumulation of beta-catenin and enhanced lung cancer cell invasion. In addition, the encoded protein can be secreted and be involved in resistance to insulin. [provided by RefSeq, Jul 2016]
General function
Intracellular signaling cascade
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Cellular localization
Secreted, Cytoplasmic
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Ovarian function
Early embryo development
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Zbed3 participates in the subcortical maternal complex and regulates the distribution of organelles. Gao Z et al. (2017) We previously identified a subcortical maternal complex (SCMC) that is essential for early embryogenesis and female fertility in mice. However, the molecular mechanism by which the SCMC affects female fertility remains largely uncharacterized. Here, we report that a novel maternal protein, zinc finger BED-type containing 3 (Zbed3), participates in the SCMC. Depletion of maternal Zbed3 results in reduced fecundity of females, because of the impaired and delayed development in a proportion of mutant embryos. The loss of maternal Zbed3 results in asymmetric zygotic division and abnormal distributions of organelles in the affected oocytes and zygotes, similar to the phenotypes observed in females with disrupted core SCMC genes. Further investigation revealed that these phenotypes are associated with disrupted dynamics of microtubules and/or formation of cytoplasmic lattices (CPLs). The stability and localization of Zbed3 depend on, but are not required for, the formation of the SCMC. Thus, our data suggest Zbed3 as one of downstream proteins mediating SCMC functions and provide further insights into roles of the SCMC and CPLs in female fertility.//////////////////
Expression regulated by
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Ovarian localization
Oocyte
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Genomewide discovery and classification of candidate ovarian fertility genes in the mouse. Gallardo TD et al. Female infertility syndromes are among the most prevalent chronic health disorders in women, but their genetic basis remains unknown because of uncertainty regarding the number and identity of ovarian factors controlling the assembly, preservation, and maturation of ovarian follicles. To systematically discover ovarian fertility genes en masse, we employed a mouse model (Foxo3) in which follicles are assembled normally but then undergo synchronous activation. We developed a microarray-based approach for the systematic discovery of tissue-specific genes and, by applying it to Foxo3 ovaries and other samples, defined a surprisingly large set of ovarian factors (n = 348, approximately 1% of the mouse genome). This set included the vast majority of known ovarian factors, 44% of which when mutated produce female sterility phenotypes, but most were novel. Comparative profiling of other tissues, including microdissected oocytes and somatic cells, revealed distinct gene classes and provided new insights into oogenesis and ovarian function, demonstrating the utility of our approach for tissue-specific gene discovery. This study will thus facilitate comprehensive analyses of follicle development, ovarian function, and female infertility. This is an oocyte-specific gene.