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PubMed2005

Structure and function of CLCA proteins.

CLCA proteins were discovered in bovine trachea and named for a calcium-dependent chloride conductance found in trachea and in other secretory epithelial tissues. At least four closely located gene loci in the mouse and the human code for independent isoforms of CLCA proteins. Full-length CLCA proteins have an unprocessed mass ratio of approximately 100 kDa. Three of the four human loci code for the synthesis of membrane-associated proteins. CLCA proteins affect chloride conductance, epithelial secretion, cell-cell adhesion, apoptosis, cell cycle control, mucus production in asthma, and blood pressure. There is a structural and probable functional divergence between CLCA isoforms containing or not containing beta4-integrin binding domains. Cell cycle control and tumor metastasis are affected by isoforms with the binding domains. These isoforms are expressed prominently in smooth muscle, in some endothelial cells, in the central nervous system, and also in secretory epithelial cells. The isoform with disrupted beta4-integrin binding (hCLCA1, pCLCA1, mCLCA3) alters epithelial mucus secretion and ion transport processes. It is preferentially expressed in secretory epithelial tissues including trachea and small intestine. Chloride conductance is affected by the expression of several CLCA proteins. However, the dependence of the resulting electrical signature on the expression system rather than the CLCA protein suggests that these proteins are not independent Ca2+-dependent chloride channels, but may contribute to the activity of chloride channels formed by, or in conjunction with, other proteins.

Amino Acid Sequence↗
PubMed2006

Survivin and Granzyme B-induced apoptosis, a novel anticancer therapy.

Survivin is an antiapoptotic protein highly expressed in malignant cells that confers resistance to cytotoxic therapy. Granzyme B is a potent cytotoxic protein that is released from mammalian natural killer cells and CTLs following noxious stimuli, including foreign invaders. Here, we took advantage of the properties of these two functionally divergent molecules to create a molecular agent that specifically activates Granzyme B within tumor cells. We designed Survivin and Granzyme B-induced apoptosis (SAGA), which consists of a fusion of the Survivin gene promoter to the coding sequence of active Granzyme B. In cultured human tumor cells transfected with SAGA DNA, Granzyme B is rapidly expressed and results in significant tumor cell death. In vivo, mice harboring human ovarian tumors had statistically significant clinical responses to SAGA treatment that were magnified following combination therapy with SAGA and paclitaxel. At the completion of a 3-week therapeutic trial, 3 of 15 animals were free of disease in the SAGA-treated group, and an additional eight animals had tumors that were nonpalpable and only detected on surgical resection. In contrast, 15 of 15 animals in the control and paclitaxel-only-treated groups had tumors at end of therapy. Treatment with SAGA with or without paclitaxel also prevented disease dissemination in 19 of 20 animals. These results strongly suggest that SAGA has the potential to be a potent agent for the treatment of primary and recurrent human ovarian carcinoma. Moreover, we predict that SAGA will be useful therapeutically in any human cancer that expresses Survivin.

Animals↗
PubMed1998

Molecular evolution of the brain of chordates.

The molecular basis of regionalisation and patterning of the developing brain is an area of current intense interest. Members of the Otx, Pax-2/5/8 and Hox gene families appear to play important roles in these processes in vertebrates, but functional divergence and genetic redundancy arising from gene duplication events obscures our view of the roles played by these genes during the evolution of vertebrate brains. Determination of the ancestral gene copy number in chordates through molecular phylogenetics, accompanied by gene expression analysis in all three chordate subphyla (vertebrates, cephalochordates and urochordates) may distinguish between ancestral and derived expression domains and give clues to the roles played by these genes in chordate ancestors. Application of this comparative approach indicates evolutionary homologous brain regions (fore-/midbrain, isthmus/cerebellum and hindbrain) in chordates and supports homology of the frontal eye of cephalochordates to the paired eyes of vertebrates.

Animals↗
PubMed2004

Physiological growth synergizes with pathological genes in experimental cardiomyopathy.

Hundreds of signaling molecules have been assigned critical roles in the pathogenesis of myocardial hypertrophy and heart failure based on cardiac phenotypes from alpha-myosin heavy chain-directed overexpression mice. Because permanent ventricular transgene expression in this system begins during a period of rapid physiological neonatal growth, resulting phenotypes are the combined consequences of transgene effects and normal trophic influences. We used temporally-defined forced gene expression to investigate synergy between postnatal physiological cardiac growth and two functionally divergent cardiomyopathic genes. Phenotype development was compared various times after neonatal (age 2 to 3 days) and adult (age 8 weeks) expression. Proapoptotic Nix caused ventricular dilation and severe contractile depression in neonates, but not adults. Myocardial apoptosis was minimal in adults, but was widespread in neonates, until it spontaneously resolved in adulthood. Unlike normal postnatal cardiac growth, concurrent left ventricular pressure overload hypertrophy did not synergize with Nix expression to cause cardiomyopathy or myocardial apoptosis. Prohypertrophic Galphaq likewise caused eccentric hypertrophy, systolic dysfunction, and pathological gene expression in neonates, but not adults. Thus, normal postnatal cardiac growth can be an essential cofactor in development of genetic cardiomyopathies, and may confound the interpretation of conventional alpha-MHC transgenic phenotypes.

Amino Acid Sequence↗
PubMed2002

Cell-based high-throughput screening assay system for monitoring G protein-coupled receptor activation using beta-galactosidase enzyme complementation technology.

A novel cell-based functional assay to directly monitor G protein-coupled receptor (GPCR) activation in a high-throughput format, based on a common GPCR regulation mechanism, the interaction between beta-arrestin and ligand-activated GPCR, is described. A protein-protein interaction technology, the InteraX trade mark system, uses a pair of inactive beta-galactosidase (beta-gal) deletion mutants as fusion partners to the protein targets of interest. To monitor GPCR activation, stable cell lines expressing both GPCR- and beta-arrestin-beta-gal fusion proteins are generated. Following ligand stimulation, beta-arrestin binds to the activated GPCR, and this interaction drives functional complementation of the beta-gal mutant fragments. GPCR activation is measured directly by quantitating restored beta-gal activity. The authors have validated this assay system with two functionally divergent GPCRs: the beta2-adrenergic amine receptor and the CXCR2 chemokine-binding receptor. Both receptors are activated or blocked with known agonists and antagonists in a dose-dependent manner. The beta2-adrenergic receptor cell line was screened with the LOPAC trade mark compound library to identify both agonists and antagonists, validating this system for high-throughput screening performance in a 96-well microplate format. Hit specificity was confirmed by quantitating the level of cAMP. This assay system has also been performed in a high-density (384-well) microplate format. This system provides a specific, sensitive, and robust methodology for studying and screening GPCR-mediated signaling pathways.

Arrestins↗
PubMed2002

Impaired expression of peroxiredoxin 4 in damaged testes by artificial cryptorchidism.

Peroxiredoxins (Prx) are a recently identified family of proteins that have been shown to exhibit peroxidase activity, as well as other divergent functions. Of the six known members of the family, Prx4 is present as a secretable form in most tissues and as a membrane-bound form only in testes. We recently proposed that the unprocessed form may be involved in acrosome formation during spermiogenesis. In the present study, it was found that levels of the unprocessed Prx4 decreased during cryptorchidism and this decrease corresponded to the degree of the defect in spermiogenesis. In contrast, the levels of the secretable Prx4 remained virtually the same during cryptorchidism. These results were consistent with selective expression of the unprocessed form after the spermatid stage, suggesting the existence of a relationship with acrosome formation.

Animals↗
PubMed2006

In silico identification and comparative analysis of differentially expressed genes in human and mouse tissues.

BACKGROUND: Screening for differentially expressed genes on the genomic scale and comparative analysis of the expression profiles of orthologous genes between species to study gene function and regulation are becoming increasingly feasible. Expressed sequence tags (ESTs) are an excellent source of data for such studies using bioinformatic approaches because of the rich libraries and tremendous amount of data now available in the public domain. However, any large-scale EST-based bioinformatics analysis must deal with the heterogeneous, and often ambiguous, tissue and organ terms used to describe EST libraries. RESULTS: To deal with the issue of tissue source, in this work, we carefully screened and organized more than 8 million human and mouse ESTs into 157 human and 108 mouse tissue/organ categories, to which we applied an established statistic test using different thresholds of the p value to identify genes differentially expressed in different tissues. Further analysis of the tissue distribution and level of expression of human and mouse orthologous genes showed that tissue-specific orthologs tended to have more similar expression patterns than those lacking significant tissue specificity. On the other hand, a number of orthologs were found to have significant disparity in their expression profiles, hinting at novel functions, divergent regulation, or new ortholog relationships. CONCLUSION: Comprehensive statistics on the tissue-specific expression of human and mouse genes were obtained in this very large-scale, EST-based analysis. These statistical results have been organized into a database, freely accessible at our website http://gln.ibms.sinica.edu.tw/product/HMDEG/EST/index.php, for easy searching of human and mouse tissue-specific genes and for investigating gene expression profiles in the context of comparative genomics. Comparative analysis showed that, although highly tissue-specific genes tend to exhibit similar expression profiles in human and mouse, there are significant exceptions, indicating that orthologous genes, while sharing basic genomic properties, could result in distinct phenotypes.

Animals↗
PubMed2006

Characterization of novel elongated Parvulin isoforms that are ubiquitously expressed in human tissues and originate from alternative transcription initiation.

BACKGROUND: The peptidyl prolyl cis/trans isomerase (PPIase) Parvulin (Par14/PIN4) is highly conserved in all metazoans and is assumed to play a role in cell cycle progression and chromatin remodeling. It is predominantly localized to the nucleus and binds to chromosomal DNA as well as bent oligonucleotides in vitro. RESULTS: In this study we confirm by RT-PCR the existence of a longer Parvulin isoform expressed in all tissues examined so far. This isoform contains a 5' extension including a 75 bp extended open reading frame with two coupled SNPs leading to amino acid substitutions Q16R and R18S. About 1% of all Parvulin mRNAs include the novel extension as quantified by real-time PCR. The human Parvulin promoter is TATA-less and situated in a CpG island typical for house keeping genes. Thus, different Parvulin mRNAs seem to arise by alternative transcription initiation. N-terminally extended Parvulin is protected from rapid proteinaseK degradation. In HeLa and HepG2 cell lysates two protein species of about 17 and 28 KDa are detected by an antibody against an epitope within the N-terminal extension. These two bands are also recognized by an antibody towards the PPIase domain of Parvulin. The longer Parvulin protein is encoded by the human genome but absent from rodent, bovine and non-mammalian genomes. CONCLUSION: Due to its molecular weight of 16.6 KDa we denote the novel Parvulin isoform as Par17 following the E. coli Par10 and human Par14 nomenclature. The N-terminal elongation of Par17-QR and Par17-RS suggests these isoforms to perform divergent functions within the eukaryotic cell than the well characterized Par14.

Amino Acid Sequence↗
PubMed2005

An inactivated nuclease-like domain in RecC with novel function: implications for evolution.

BACKGROUND: The PD-(D/E)xK superfamily, containing a wide variety of other exo- and endonucleases, is a notable example of general function conservation in the face of extreme sequence and structural variation. Almost all members employ a small number of shared conserved residues to bind catalytically essential metal ions and thereby effect DNA cleavage. The crystal structure of the RecBCD prokaryotic DNA repair machinery shows that RecB contains such a nuclease domain at its C-terminus. The RecC C-terminal region was reported as having a novel fold. RESULTS: The RecC C-terminal region can be divided into an alpha/beta domain and a smaller alpha-helical bundle domain. Here we show that the alpha/beta domain is homologous to the RecB nuclease domain but lacks the features necessary for catalysis. Instead, the domain has a novel function within the nuclease superfamily--providing a hoop through which single-stranded DNA passes. Comparison with other structures of nuclease domains bound to DNA reveals strikingly different modes of ligand binding. The alpha-helical bundle domain contributes the pin which splits the DNA duplex. CONCLUSION: The demonstrated homology of RecB and RecC shows how evolution acted to produce the present RecBCD complex through aggregation of new domains as well as functional divergence and structural redeployment of existing domains. Distantly homologous nuclease(-like) domains bind DNA in highly diverse manners.

Amino Acid Sequence↗
PubMed2002

All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction.

The tumor necrosis factor (TNF) receptor associated factors (TRAFs) have emerged as the major signal transducers for the TNF receptor superfamily and the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily. TRAFs collectively play important functions in both adaptive and innate immunity. Recent functional and structural studies have revealed the individuality of each of the mammalian TRAFs and advanced our understanding of the underlying molecular mechanisms. Here, we examine this functional divergence among TRAFs from a perspective of both upstream and downstream TRAF signal transduction pathways and of signaling-dependent regulation of TRAF trafficking. We raise additional questions and propose hypotheses regarding the molecular basis of TRAF signaling specificity.

Amino Acid Sequence↗
PubMed1999

Nucleocytoplasmic protein transport and recycling of Ran.

The active transport of proteins into and out of the nucleus is mediated by specific signals, the nuclear localization signal (NLS) and nuclear export signal (NES), respectively. The best characterized NLS is that of the SV40 large T antigen, which contains a cluster of basic amino acids. The NESs were first identified in the protein kinase inhibitor (PKI) and HIV Rev protein, which are rich in leucine residues. The SV40 T-NLS containing transport substrates are carried into the nucleus by an importin alpha/beta heterodimer. Importin alpha recognizes the NLS and acts as an adapter between the NLS and importin beta, whereas importin beta interacts with importin alpha bound to the NLS, and acts as a carrier of the NLS/importin alpha/beta trimer. It is generally thought that importin alpha and beta are part of a large protein family. The leucine rich NES-containing proteins are exported from the nucleus by one of the importin beta family molecules, CRM1/exportin 1. A Ras-like small GTPase Ran plays a crucial role in both import/export pathways and determines the directionality of nuclear transport. It has recently been demonstrated in living cells that Ran actually shuttles between the nucleus and the cytoplasm and that the recycling of Ran is essential for the nuclear transport. Furthermore, it has been shown that nuclear transport factor 2 (NTF2) mediates the nuclear import of RanGDP. This review largely focuses on the issue concerning the functional divergence of importin alpha family molecules and the role of Ran in nucleocytoplasmic protein transport.

Animals↗
PubMed2006

Understanding the basis for Down syndrome phenotypes.

Down syndrome is a collection of features that are caused by trisomy for human Chromosome 21. While elevated transcript levels of the more than 350 genes on the chromosome are primarily responsible, it is likely that multiple genetic mechanisms underlie the numerous ways in which development and function diverge in individuals with trisomy 21 compared to euploid individuals. We consider genotype-phenotype interactions with the goal of producing working concepts that will be useful for approaches to ameliorate the effects of trisomy.

Alleles↗
PubMed2026

Balancing under constraint: Structural insights into norovirus evolution and antigenic innovation.

Norovirus is the leading cause of acute viral gastroenteritis worldwide. While genomic studies have revealed its diversity and evolutionary patterns, the structural mechanisms driving viral adaptation remain poorly understood. Here, we establish a comprehensive structural database of norovirus VP1 P-domains across nine genogroups (GI-GIX) through large-scale AlphaFold2 predictions. By integrating phylogenetic analysis of VP1 sequences and structures, we demonstrate that sequence and structural evolution show overall concordance under purifying selection, yet significant local discrepancies reveal distinct patterns of convergent evolution shaped by structural constraints and functional divergence. Focusing on the predominant GII.4 genotype, we found that compared to near-full-genome and nucleotide trees, only the VP1 amino acid tree reliably clustered GII.4 variants in chronological order as monophyletic groups. We further identify a hierarchical evolutionary strategy: positive selection may drive structural hypervariability in major antigenic epitopes D and C for immune escape, with epitope D exhibiting pronounced structural flexibility that complicates its structural characterization, whereas coevolutionary analysis uncovers a broad network of compensatory interactions spanning multiple epitopes, with striking enrichment in epitope A. These epitopes exhibited a pattern of "sequence plasticity with structural conservation", maintained by coevolutionary constraints that preserve conformational integrity. Together, these findings suggest that norovirus vaccine strategies targeting the structurally conserved conformations of epitopes A and G could overcome the limitations of traditional strain-specific approaches, offering a pathway toward broad protection against evolving viral diversity.

Norovirus↗
PubMed2026

Systematic profiling of nudivirus-like genes reveals conserved and differentiated roles in a domesticated endogenous virus.

Cotesia vestalis bracovirus (CvBV) is a type of domesticated endogenous virus (DEV) derived from ancestral nudiviruses that is integrated into the genome of the parasitoid wasp Cotesia vestalis. The CvBV proviral genome is composed of two distinct components: one encoding genes associated with virion morphogenesis and assembly, and the other harboring virulence genes that are excised, circularized, and packaged into virions. CvBV replication and particle assembly occur exclusively in the ovaries of female wasps. While prior studies have largely focused on the function of virulence genes during parasitization, the molecular mechanisms underlying CvBV replication and assembly remain poorly understood. Here, we identified 71 nudivirus-like genes in the C. vestalis genome through integrated transcriptomic and proteomic analyses. Using gene silencing and microscopy-based imaging approaches, we functionally characterized 24 key genes involved in DNA replication (helicase, integrase-1, and integrase-2), transcriptional regulation (p47, lef-5, and lef-9), capsid formation (vp39, PmV, HzNVorf9-1, HzNVorf9-2, HzNVorf106, 38k, 27b, and K425_459), envelope formation (11k, 17a-1, 35a-1, 35a-2, and K425_461), virion assembly (vlf-1, HzNVorf140-1, and HzNVorf140-2), and viral infectivity (pif-0 and vp91). Although the functions of most nudivirus-like genes are generally conserved among baculoviruses, nudiviruses, and bracoviruses, lef-5, K425_459, 11k, and vp91 appear to have undergone functional divergence relative to their homologs in baculoviruses, nudiviruses, and Microplitis demolitor bracovirus, highlighting lineage-specific adaptations in CvBV. Collectively, our work provides a molecular framework for understanding CvBV assembly and serves as a valuable resource for investigating bracovirus evolution.

Animals↗
PubMed1995

The follicle-stimulating hormone receptor and luteinizing hormone receptor genes are closely linked in sheep and deer.

Restriction fragment length polymorphisms were identified in sheep and deer using ovine cDNA probes for the FSH receptor (FSHR) and the LH receptor (LHCGR). FSHR and LHCGR were closely linked in sheep with no recombinants and neither receptor was linked to the Booroola fecundity gene (FecB). Both receptors were also closely linked in deer at a map distance of 3.3 cM. Linkage between the receptor genes assigns FSHR to sheep chromosome 3. Sequence analysis showed that the mammalian LHCGRs and FSHRs are more similar to each other than to mammalian TSH receptor (TSHR). Taken together, these data suggest that TSHR and the LHCGR/FSHR arose from a common ancestral gene by a process of chromosomal duplication. Subsequent duplication of the region containing the LH/FSH receptor and functional divergence could have given rise to the two gonadotrophin receptors present in mammals today.

Alleles↗
PubMed2004

Effect of a glycine residue insertion into crustacean hyperglycemic hormone on hormonal activity.

Crustacean hyperglycemic hormone (CHH) and molt-inhibiting hormone (MIH) have similar amino acid sequences and therefore comprise a peptide family referred to as the CHH family. All MIHs unexceptionally have an additional glycine residue at position 12, which is lacking in all CHHs. In order to understand the relevance of the absence of the glycine residue for hyperglycemic activity, a mutant CHH having a glycine residue insertion was prepared, and its hyperglycemic activity was assessed. This mutant CHH had the same disulfide bond arrangement as the recombinant CHH produced in Escherichia coli cells, and exhibited a similar circular dichroism spectrum to the recombinant CHH, indicating that the two CHHs possessed similar conformations. The mutant CHH showed a hyperglycemic effect weaker than the recombinant CHH by about one order of magnitude. These results suggest that the insertion of a glycine residue is one of the indices for structural and functional divergence of the CHH family peptides.

Amino Acid Sequence↗
PubMed2026

Genome-Wide Identification of the LdARF Gene Family in Lilium davidii var. unicolor and Transient Functional Analysis of LdARF17 in Bulblet Regeneration.

Auxin response factors (ARFs) are key transcriptional regulators of the auxin signaling pathway and play important roles in plant organogenesis and regeneration. However, the functions of ARF family genes in lily scale-derived bulblet regeneration remain largely unclear. In this study, 24 LdARF genes were identified from the genome of Lilium davidii var. unicolor. Phylogenetic analysis revealed that LdARF proteins showed evolutionary conservation with ARF homologs from other monocot species. Genome-wide identification, phylogenetic analysis, and expression profiling revealed functional divergence among LdARF genes during scale-derived bulblet regeneration. Among them, LdARF17 exhibited a distinct regeneration-associated expression pattern, characterized by rapid induction after scale excision and sustained high expression during subsequent bulblet initiation and formation. Subcellular localization analysis demonstrated that LdARF17 is localized in the nucleus. Transient overexpression of LdARF17 significantly promoted bulblet regeneration and was associated with increased expression of auxin-responsive and regeneration-related genes, including IAA14, LBD16, and LBD29. These findings suggest that LdARF17 acts as a positive regulator of lily scale regeneration and may influence auxin-responsive transcriptional processes associated with early cell proliferation, providing new insights into the molecular mechanisms underlying vegetative regeneration in lilies.

Auxin response factor↗
PubMed2003

IL-1 receptor-associated kinase 4 is essential for IL-18-mediated NK and Th1 cell responses.

IL-18 is an important cytokine for both innate and adaptive immunity. NK T cells and Th1 cells depend on IL-18 for their divergent functions. The IL-18R, IL-1R, and mammalian Toll-like receptors (TLRs) share homologous intracellular domains known as the TLR/IL-1R/plant R domain. Previously, we reported that IL-1R-associated kinase (IRAK)-4 plays a critical role in IL-1R and TLR signaling cascades and is essential for the innate immune response. Because TLR/IL-1R/plant R-containing receptors mediate signal transduction in a similar fashion, we investigated the role of IRAK-4 in IL-18R signaling. In this study, we show that IL-18-induced responses such as NK cell activity, Th1 IFN-gamma production, and Th1 cell proliferation are severely impaired in IRAK-4-deficient mice. IRAK-4(-/-) Th1 cells also do not exhibit NF-kappaB activation or IkappaB degradation in response to IL-18. Moreover, AP-1 activation which is triggered by c-Jun N-terminal kinase activation is also completely inhibited in IRAK-4(-/-) Th1 cells. These results suggest that IRAK-4 is an essential component of the IL-18 signaling cascade.

Animals↗