Phylogenetic analysis of protocadherin genes identified a new gene subfamily, the delta-protocadherins, containing several conserved motifs in their cytoplasmic domains. This subfamily can be further ...subdivided into two subgroups, named delta1-protocadherins (comprising protocadherin-1, -7, -9, and -11 or X/Y) and delta2-protocadherins (comprising protocadherin-8, -10, -17, -18, and -19). The members of the delta1-protocadherin subgroup were analyzed in greater detail here. They share a similar gene structure that results in the expression of multiple alternative transcripts. All members of this subgroup have at least one transcript that contains a binding site for protein phosphatase-1alpha. Like most classic cadherins, each of three delta1-protocadherins analyzed in this study by in situ hybridization showed a unique expression pattern that differed from the patterns of the other delta1-protocadherins. Together, these results suggest that the members of the delta1-protocadherin subgroup exercise tightly regulated functions in the development, regionalization, and functional differentiation of the mouse brain.
The Armadillo protein p120(ctn) associates with the cytoplasmic domain of cadherins and accumulates at cell-cell junctions. Particular Armadillo proteins such as beta-catenin and plakophilins show a ...partly nuclear location, suggesting gene-regulatory activities. For different human E-cadherin-negative carcinoma cancer cell lines we found expression of endogenous p120(ctn) in the nucleus. Expression of E-cadherin directed p120(ctn) out of the nucleus. Previously, we reported that the human p120(ctn) gene might encode up to 32 protein isoforms as products of alternative splicing. Overexpression of p120(ctn) isoforms B in various cell lines resulted in cytoplasmic immunopositivity but never in nuclear staining. In contrast, upon expression of p120(ctn) cDNAs lacking exon B, the isoforms were detectable within both nuclei and cytoplasm. A putative nuclear export signal (NES) with a characteristic leucine-rich motif is encoded by exon B. This sequence element was shown to be required for nuclear export and to function autonomously when fused to a carrier protein and microinjected into cell nuclei. Moreover, the NES function of endogenously or exogenously expressed p120(ctn) isoforms B was sensitive to the nuclear export inhibitor leptomycin B. Expression of exogenous E-cadherin down-regulated nuclear p120(ctn) whereas activation of protein kinase C increased the level of nuclear p120(ctn). These results reveal molecular mechanisms controlling the subcellular distribution of p120(ctn).
E-cadherin is a Ca
2+-dependent epithelial cell—cell adhesion molecule. Downregulation of E-cadherin expression often correlates with strong invasive potential and poor prognosis of human carcinomas. ...By using recombinant λ phage, cosmid, and P1 phage clones, we isolated the full-length human E-cadherin gene (CDH1). The gene spans a region of approximately 100 kb, and its location on chromosome 16q22.1 was confirmed by FISH analysis. Detailed restriction mapping and partial sequence analysis of the gene allowed us to identify 16 exons and a 65-kb-long intron 2. The intron—exon boundaries are highly conserved in comparison with other “classical cadherins.” In intron 1 we identified a 5′ high-density CpG island that may be implicated in transcription regulation during embryogenesis and malignancy.
Partial and complete genome duplications occurred during evolution and resulted in the creation of new genes and gene families. We identified a novel and intricate human gene family located primarily ...in regions of segmental duplications on human chromosome 1. We named it NBPF, for neuroblastoma breakpoint family, because one of its members is disrupted by a chromosomal translocation in a neuroblastoma patient. The NBPF genes have a repetitive structure with high intragenic and intergenic sequence similarity in both coding and noncoding regions. These similarities might expose these genomic regions to illegitimate recombination, resulting in structural variation in the NBPF genes. The encoded proteins contain a highly conserved domain of unknown function, which we have named the NBPF repeat. In silico analysis combined with the isolation of multiple full-length cDNA clones showed that several members of this gene family are abundantly expressed in a large variety of tissues and cell lines. Strikingly, no discernable orthologues could be identified in the completed genomes of fruit fly, nematode, mouse, or rat, but sequences with low homology could be isolated from the draft canine and bovine genomes. Interestingly, this gene family shows primate-specific duplications that result in species-specific arrays of NBPF homologous sequences. Overall, this novel NBPF family reflects the continuous evolution of primate genomes that resulted in large physiological differences, and its potential role in this process is discussed.
The Armadillo protein p120ctn associates with the cytoplasmic domain of cadherins and accumulates at cell-cell junctions. Particular Armadillo proteins such as β -catenin and plakophilins show a ...partly nuclear location, suggesting gene-regulatory activities. For different human E-cadherin-negative carcinoma cancer cell lines we found expression of endogenous p120ctn in the nucleus. Expression of E-cadherin directed p120ctn out of the nucleus. Previously, we reported that the human p120ctn gene might encode up to 32 protein isoforms as products of alternative splicing. Overexpression of p120ctn isoforms B in various cell lines resulted in cytoplasmic immunopositivity but never in nuclear staining. In contrast, upon expression of p120ctn cDNAs lacking exon B, the isoforms were detectable within both nuclei and cytoplasm. A putative nuclear export signal (NES) with a characteristic leucine-rich motif is encoded by exon B. This sequence element was shown to be required for nuclear export and to function autonomously when fused to a carrier protein and microinjected into cell nuclei. Moreover, the NES function of endogenously or exogenously expressed p120ctn isoforms B was sensitive to the nuclear export inhibitor leptomycin B. Expression of exogenous E-cadherin down-regulated nuclear p120ctn whereas activation of protein kinase C increased the level of nuclear p120ctn. These results reveal molecular mechanisms controlling the subcellular distribution of p120ctn
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