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Query: UNIPROT:P06889 (Mol)
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The first tier of control over the expression of genic domains utilizes chromatin structure. Before the onset of transcription, the chromatin domain that encompasses the gene(s) must assume an open conformation. This renders large segments of the genome available to the tissue-specific and ubiquitous trans-factors necessary for proper expression of the genes present. This process has been termed potentiation. It is a necessary obligate, but alone it is not sufficient for gene expression. Spermatogenesis, the development of a viable fertile male gamete, provides a unique model to begin to address the underlying mechanism(s) governing differentiation and tissue-specific gene expression. Male gametogenesis is typified by the activation of numerous genes whose products have novel functions, as well as testis-specific forms of constitutively expressed somatic genes. We have shown that mouse spermatogenesis represents a selective potentiative process (Kramer et al., 1998: Development 125:4749-4655), but little is known about its human counterpart. To fill this void we have examined the potentiative state of several spermatid-expressed genes during the latter stages of human spermatogenesis. We have shown that spermatidexpressed genes are potentiated by the pachytene stage of differentiation. Furthermore, we establish that a chromatin domain functions as a discrete structural unit during differentiation. Interestingly, some of these open structures are maintained in the mature spermatozoon.
Mol Reprod Dev 2000 Jun
PMID:Human spermatogenesis as a model to examine gene potentiation. 1082 79

Ubiquitin-specific processing proteases (UBPs) presently form the largest enzyme family in the ubiquitin system, characterized by a core region containing conserved motifs surrounded by divergent sequences, most commonly at the N-terminal end. The functions of these divergent sequences remain unclear. We identified two isoforms of a novel testis-specific UBP, UBP-t1 and UBP-t2, which contain identical core regions but distinct N termini, thereby permitting dissection of the functions of these two regions. Both isoforms were germ cell specific and developmentally regulated. Immunocytochemistry revealed that UBP-t1 was induced in step 16 to 19 spermatids while UBP-t2 was expressed in step 18 to 19 spermatids. Immunoelectron microscopy showed that UBP-t1 was found in the nucleus while UBP-t2 was extranuclear and was found in residual bodies. For the first time, we show that the differential subcellular localization was due to the distinct N-terminal sequences. When transfected into COS-7 cells, the core region was expressed throughout the cell but the UBP-t1 and UBP-t2 isoforms were concentrated in the nucleus and the perinuclear region, respectively. Fusions of each N-terminal end with green fluorescent protein yielded the same subcellular localization as the native proteins, indicating that the N-terminal ends were sufficient for determining differential localization. Interestingly, UBP-t2 colocalized with anti-gamma-tubulin immunoreactivity, indicating that like several other components of the ubiquitin system, a deubiquitinating enzyme is associated with the centrosome. Regulated expression and alternative N termini can confer specificity of UBP function by restricting its temporal and spatial loci of action.
Mol Cell Biol 2000 Sep
PMID:Divergent N-terminal sequences target an inducible testis deubiquitinating enzyme to distinct subcellular structures. 1093 31

Deletions of the AZFc interval of the human Y chromosome are found in >5% of male patients with idiopathic infertility and are associated with a severely reduced sperm count. The most common deletion type is large (>1 Mb) and removes members of the Y-borne testis-specific gene families of BPY2, CDY1, DAZ, PRY, RBMY2 and TTY2, which are candidate AZF genes. Four exceptional individuals who have transmitted a large AZFc deletion naturally to their infertile sons have, however, been described. In three cases, transmission was to an only son, but in the fourth case a Y chromosome, shown to be deleted for all copies of DAZ, was transmitted from a father to his four infertile sons. Here we present a second family of this latter type and demonstrate that an AZFc-deleted Y chromosome lacking not only DAZ, but also BPY2 and CDY1, has been transmitted from a father to his three infertile sons. Polymerase chain reaction (PCR) and Southern blot analyses revealed no difference in the size of the AZFc deletion in the father and his sons. We propose that the father carries rare alleles of autosomal or X-linked loci which suppress the infertility that is frequently associated with the absence of AZFc.
Mol Hum Reprod 2000 Sep
PMID:The human Y chromosome genes BPY2, CDY1 and DAZ are not essential for sustained fertility. 1095 50

The gene encoding heterogeneous ribonucleoprotein (hnRNP) G recently has been mapped to the X chromosome. All mammals have a Y chromosome-encoded homologue of HNRNP G called RBMY, which is implicated with a role in male fertility and is a candidate for the azoospermia factor gene. We have identified a new member of this gene family, HNRNP G-T, and have mapped it as a single-copy gene on chromosome 11. This gene contains an uninterrupted open reading frame and no introns, consistent with derivation from a retroposon. However, unlike many retroposon-derived genes, HNRNP G-T is not a pseudogene. An antiserum raised to the conceptual reading frame of HNRNP G-T showed that it encodes a protein that is highly expressed in germ cells and in particular in the nuclei of meiotic spermatocytes. Surprisingly, although this antiserum was raised against human hnRNP G-T protein, it can also detect a similar protein in the testis of several mammals. This suggests that the protein is highly conserved and that the retrotransposition event generating the HNRNP G-T gene pre-dated at least the common ancestor of mouse and man. The existence of an additional testis-specific hnRNP G family member provides evidence for the importance of these proteins in normal germ cell development.
Hum Mol Genet 2000 Sep 01
PMID:An evolutionarily conserved germ cell-specific hnRNP is encoded by a retrotransposed gene. 1095 50

Jingwei (jgw) is the first gene found to be of sufficiently recent origin in Drosophila to offer insights into the origin of a gene. While its chimerical gene structure was partially resolved as including a retrosequence of alcohol dehydrogenase (ADH:), the structure of its non-ADH: parental gene, the donor of the N-terminal domain of jgw, is unclear. We characterized this non-ADH: parental locus, yellow emperor (ymp), by cloning it, mapping it onto the polytene chromosomes, sequencing the entire locus, and examining its expression patterns in Drosophila melanogaster. We show that ymp is located in the 96-E region; the N-terminal domain of ymp has donated the non-ADH: portion of jgw via a duplication. The similar 5' portions of the gene and its regulatory sequences give rise to similar testis-specific expression patterns in ymp and jgw in Drosophila teissieri. Furthermore, between-species comparison of ymp revealed purifying selection in the protein sequence, suggesting a functional constraint in ymp. While the structure of ymp provides clear information for the molecular origin of the new gene jgw, it unexpectedly casts a new light on the concept of genes. We found, for the first time, that the single locus of the ymp gene encompasses three major molecular mechanisms determining structure of eukaryotic genes: (1) the 5' exons of ymp are involved in an exon-shuffling event that has created the portion recruited by jgw; (2) using alternative cleavage sites and alternative splicing sites, the 3' exon groups of ymp produce two proteins with nonhomologous C-terminal domains, both exclusively in the testis; and (3) in the opposite strand of the third intron of ymp is an essential gene, musashi (msi), which encodes an RNA-binding protein. The composite gene structure of ymp manifests the complexity of the gene concept, which should be considered in genomic research, e.g., gene finding.
Mol Biol Evol 2000 Sep
PMID:The origin of the Jingwei gene and the complex modular structure of its parental gene, yellow emperor, in Drosophila melanogaster. 1095 46

We have previously cloned a cDNA encoding TBP-1, a protein present in the rat spermatid manchette and outer dense fibers of the developing sperm. TBP-1 contains a heptad repeat of six-leucine zipper fingers at the amino terminus and highly conserved ATPase and DNA/RNA helicase motifs toward the carboxyl terminus. TBP-1 is one of the 20 subunits forming the 19S regulatory complex of the 26S proteasome, an ATP-dependent multisubunit protease found in most eukaryotic cells. We now report the isolation of the 26S proteasome from rat testis and sperm tail and its visualization by whole-mount electron microscopy using negative staining. The 26S proteasome from rat testis was fractionated by Sephacryl S-400/Mono-Q chromatography using homogenates suspended in a 10% glycerol-supplemented buffer. Chromatographic fractions were analyzed by immunoblotting using a specific anti-TBP-1 serum. During the purification of Sak57, a keratin filament present in outer dense fibers from epididymal sperm, we detected a substantial amount of 26S proteasomes. Intact 26S proteasomes from rat testis display a rod-shaped particles about 45 nm in length and 11-17 nm in diameter. Each particle consists of a 20S barrel-shaped component formed by four rings (alphabetabetaalpha), capped by two polar 19S regulatory complexes, each identified by an element known as the "Chinese dragon head motif". TBP-1 is an ATPase-containing subunit of the 19S regulatory cap. Rat sperm preparations displayed both dissociated 26S proteasomes and Sak57 filaments. We hypothesize that 26S proteasomes in the perinuclear-arranged manchette are in a suitable location for recognition, sequestration, and degradation of accumulating ubiquitin-conjugated somatic and transient testis-specific histones during spermiogenesis. In the sperm tail, the 26S proteasome may have a role in the remodeling of the outer dense fibers and other tail components during epididymal transit.
Mol Reprod Dev 2000 Oct
PMID:Structural features of the 26S proteasome complex isolated from rat testis and sperm tail. 1098 18

The human growth hormone/placental lactogen (GH/PL) gene cluster consists of five highly-related genes (GH-N, GH-V, PL-L, PL-A, PL-B). This evolutionarily young gene cluster codes for an array of mRNAs and proteins, such as the major 22 k forms (hGH-N/V, identical PL-A and B), 20 k and 17.5 k hGH-N and the recently described 25 k hGH-Delta4, a presumably chimeric molecule. In addition, two longer alternatively spliced, (intron D retaining) mRNAs isoforms, termed PL-A2 and GH-V2, have been described in placenta and testis. To elucidate the role of hPL-A2 in male reproduction and pregnancy, testicular PL-A2 cDNA was cloned in a complementary overlapping 2-way RT-PCR approach to analyze translation, localization and structure/function of this unusual member of the GH/PL growth factor family. Analysis of insect mRNA revealed that intron D-retaining PL-A2 cDNA was expressed without splicing in the baculovirus expression system. Thus, PL-A2 mRNA does not represent a nuclear intermediate splicing product simply co-isolated with the mature RNA, but is a stable mRNA isoform generated by placental/testis-specific splicing factors. Recombinant protein was present in whole cell extracts, and no secreted protein was detected in the supernatant. Immunologically, the N-terminus of the 230 amino acid protein is similar to 22 k hPL-A/B, as determined by hPL-specific monoclonal antibodies. In contrast, the C-terminus shares a hydrophobic region presumably responsible for membrane insertion. By the use of confocal microscopy recombinant hPL-A2 was localized in the cell membrane. Thus, hPL-A2 might exert its function by modulating GH/PL actions or act as an independent growth-regulatory molecule itself and its functions in male reproduction and embryonic development remain to be investigated.
Mol Cell Endocrinol 2000 Sep 25
PMID:An unusual member of the human growth hormone/placental lactogen (GH/PL) family, the testicular alternative splicing variant hPL-A2: recombinant expression revealed a membrane-associated growth factor molecule. 1100 May 26

The ubiquitous Fer protein-tyrosine kinase has been proposed to regulate diverse processes such as cell growth, cell adhesion, and neurite outgrowth. To gain insight into the biological function of Fer, we have targeted the fer locus with a kinase-inactivating missense mutation (fer(D743R)). Mice homozygous for this mutation develop normally, have no overt phenotypic differences from wild-type mice, and are fertile. Since these mice lack both Fer and the testis-specific FerT kinase activities, these proteins are clearly not essential for development and survival. No differences were observed in overall cellularity of bone marrow, spleen, or thymus in the absence of Fer activity. While most platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation was unchanged in fer(D743R) homozygous embryonic fibroblasts, cortactin phosphorylation was reduced. However, Fer kinase activity was not required for PDGF-induced Stat3, p120(ctn), or epidermal growth factor (EGF)-induced beta-catenin phosphorylation. Also, no defects were observed in changes to the actin cytoskeleton, adherens junctions, or focal adhesions in PDGF- or EGF-stimulated fer(D743R) homozygous embryonic fibroblasts. Therefore, Fer likely serves a redundant role in regulating cell growth, cell adhesion, retinal development, and spermatogenesis but is required for efficient phosphorylation of cortactin.
Mol Cell Biol 2001 Jan
PMID:Mice devoid of fer protein-tyrosine kinase activity are viable and fertile but display reduced cortactin phosphorylation. 1113 46

Evidence for the importance of genetic factors in male fertility is accumulating. In the literature and the Mendelian Cytogenetics Network database, 265 cases of infertile males with balanced reciprocal translocations have been described. The candidacy for infertility of 14 testis-expressed transcripts (TETs) were examined by comparing their chromosomal mapping position to the position of balanced reciprocal translocation breakpoints found in the 265 infertile males. The 14 TETs were selected by using digital differential display (electronic subtraction) to search for apparently testis-specific transcripts in the TIGR database. The testis specificity of the 14 TETs was further examined by reverse transcription-polymerase chain reaction (RT-PCR) on adult and fetal tissues showing that four TETs (TET1 to TET4) were testis-expressed only, six TETs (TET5 to TET10) appeared to be differentially expressed and the remaining four TETs (TET11 to TET14) were ubiquitously expressed. Interestingly, the two tesis expressed-only transcripts, TET1 and TET2, mapped to chromosomal regions where seven and six translocation breakpoints have been reported in infertile males respectively. Furthermore, one ubiquitously, but predominantly testis-expressed, transcript, TET11, mapped to 1p32-33, where 13 translocation breakpoints have been found in infertile males. Interestingly, the mouse mutation, skeletal fusions with sterility, sks, maps to the syntenic region in the mouse genome. Another transcript, TET7, was the human homologue of rat Tpx-1, which functions in the specific interaction of spermatogenic cells with Sertoli cells. TPX-1 maps to 6p21 where three cases of chromosomal breakpoints in infertile males have been reported. Finally, TET8 was a novel transcript which in the fetal stage is testis-specific, but in the adult is expressed in multiple tissues, including testis. We named this novel transcript fetal and adult testis-expressed transcript (FATE).
Mol Hum Reprod 2001 Jan
PMID:Identification of human candidate genes for male infertility by digital differential display. 1113 55

Genes involved in male fertility are potential targets for sexual selection, and their evolution may play a role in reproductive isolation and speciation. Here we describe a new Drosophila melanogaster gene, ocnus (ocn), that encodes a protein abundant in testes nuclear extracts. RT-PCR indicates that ocn transcription is limited to males and is specific to testes. ocn shares homology with another testis-specific gene, janusB (janB), and is located just distal to janB on chromosome 3. The two genes also share homology with the adjacent janusA (janA) gene, suggesting that multiple duplication events have occurred within this region of the genome. We cloned and sequenced these three genes from species of the D. melanogaster species subgroup. Phylogenetic analysis based on protein-encoding sequences predicts a duplication pattern of janA --> janA janB --> janA janB ocn, with the latter event occurring after the divergence of the D. melanogaster and Drosophila obscura species groups. We found significant heterogeneity in the rates of evolution among the three genes within the D. melanogaster species subgroup as measured by the ratio of nonsynonymous to synonymous substitutions, suggesting that diversification of gene function followed each duplication event and that each gene evolved under different selective constraints. All three genes showed faster rates of evolution than genes encoding proteins with metabolic function. These results are consistent with previous studies that have detected an increased rate of evolution in genes with reproductive function.
Mol Biol Evol 2001 May
PMID:Molecular evolution of the ocnus and janus genes in the Drosophila melanogaster species subgroup. 1131 64


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