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PubMed2003

The sodium phosphate cotransporter family SLC34.

This review summarizes the characteristics of the solute carrier family SLC34 that is represented by the type ll Na/P(i)-cotransporters NaPi-lla (SLC34A1), NaPi-llb (SLC34A2) and NaPi-llc (SLC34A3). Other Na/P(i)-cotransporters are described within the SLC17 and SLC20 families. Type ll Na/P(i)-cotransporters are expressed in several tissues and play a major role in the homeostasis of inorganic phosphate. In kidney and small intestine, type ll Na/P(i)-cotransporters are located at the apical sites of epithelial cells and represent the rate limiting steps for transepithelial movement of phosphate. Physiological and pathophysiological regulation of renal and small intestinal epithelial transport of phosphate occurs through alterations in the abundance of type ll Na/P(i)-cotransporters.

Animals↗

PubMed1993

Primary structure and cell-type specific expression of a gustatory G protein-coupled receptor related to olfactory receptors.

We have reported on the partial structures of a multigene family encoding GTP-binding protein (G protein)-coupled, seven-transmembrane receptors expressed in the tongue (Abe, K., Kusakabe, Y., Tanemura, K., Emori, Y., and Arai, S. (1993) FEBS Lett. 316, 253-256). Here we describe a full-length cDNA clone encoding a tongue cell-type specific receptor. The encoded protein consists of 312 amino acid residues. In overall structure, the protein is similar to known G protein-coupled, seven-transmembrane receptors such as an olfactory receptor (56% identity) but is significantly different in part, particularly in NH2-terminal extracellular and COOH-terminal cytoplasmic domain structures. Northern analysis showed that the mRNA for this protein is expressed only in the epithelium of the tongue, not in other organs. In situ hybridization experiments clearly indicated that the mRNA is expressed exclusively on the tongue apical surface, not on the reverse side of the tongue nor in its muscle layer. Expression was also detected in the taste buds and surrounding cellular tissues of the fungiform and circumvallate papillae. It is suggested that this gustatory receptor structurally related to olfactory receptors may be a candidate for a taste receptor.

Amino Acid Sequence↗

PubMedDate not supplied

Murine primary in vivo response to TNP-Ficoll: multigenic control involving H-2.

Since the primary PFC response to TNP-Ficoll, a thymus-independent type 2 antigen, displays an important variability in vivo among diverse inbred mouse strains, we used, in the present report, H-2 congenic strains possessing different genetic backgrounds to show that the amplitude of this response is governed by MHC genes, with one regulating locus situated in or near the centromeric part of the I-A subregion. In addition, this H-2 control was largely modulated by gene(s) located outside MHC and IgH haplotypes, as evidenced by the response of recombinant inbred strains (BXH) between the high responder C3H/HeJ and the low responder C57BL/6J. Our results are discussed in terms of humoral regulations and the requirement for self-recognition in cellular interactions which lead to activation of B lymphocytes in the in vivo primary response towards TI-2 antigens.

Animals↗

PubMed2005

Multifaceted therapeutic approaches for a multigenic disease.

Diabetes is a severe chronic disease that affects approximately 200 million individuals worldwide, with extremely debilitating effects and considerably high health care costs. The two major classes of diabetes, known as type 1 (previously known as insulin-dependent or juvenile-onset diabetes) and type 2 (non-insulin-dependent diabetes), share common symptoms such as hyperglycemia and the development of long-term complications, but they differ in many aspects, including their etiopathogenesis. New insights suggest that overlapping factors, formerly considered typical hallmarks of each specific type, can coexist in the same diabetic patient, making it difficult to support a sharp distinction between the two classes and, more importantly, to adopt appropriate therapeutic solutions. In type 1 and type 2 diabetic subjects, but even more in patients with combined types, multiple genetic factors play a role in determining susceptibility or resistance to the disease, and perhaps also the time of onset, the severity of the symptoms, the possibility of developing complications and, ultimately, the response to therapy. In this review, the therapeutic treatments currently under investigation, as well as the curative strategies envisioned for future applications, are reanalyzed considering the multifaceted and complex aspects of a continuum that can be just defined as "diabetes."

Animals↗

PubMed1997

Autoantibodies to IA-2 and IA-2 beta in insulin-dependent diabetes mellitus recognize conformational epitopes: location of the 37- and 40-kDa fragments determined.

IA-2 and IA-2 beta are major autoantigens in insulin-dependent diabetes mellitus (IDDM) and the precursors, respectively, of a 40-and 37-kDa tryptic fragment that reacts with IDDM sera. In the present study, by amino acid sequencing of recombinant IA-2 and IA-2 beta, we determined the tryptic cleavage sites involved in the generation of these fragments. Both cleavage sites are immediately after an arginine residue at position 653 for IA-2 and position 679 for IA-2 beta. The resulting tryptic fragments are 326 and 307 amino acids in length and retain their ability to react with IDDM sera. In contrast to IA-2 and IA-2 beta, other members of the protein tyrosine phosphatase (PTP) family (i.e., RPTP kappa, RPTPmu, NU-3, SHP, and 3CH134) are completely susceptible to digestion by trypsin. Sequence analysis revealed five conserved cysteine residues in IA-2 and IA-2 beta that are not present in other PTPs. Reduction and alkylation of IA-2 and IA-2 beta recombinant proteins resulted in loss of both resistance to digestion by trypsin and reactivity with autoantibodies in IDDM sera. It is concluded that disulfide bond formation plays a critical role in the maintenance of antigenic structure and that the autoantibodies to IA-2/IA-2 beta in IDDM sera recognize conformational epitopes.

Amino Acid Sequence↗

PubMed2006

Multi-target therapeutics: when the whole is greater than the sum of the parts.

Drugs designed to act against individual molecular targets cannot usually combat multigenic diseases such as cancer, or diseases that affect multiple tissues or cell types such as diabetes and immunoinflammatory disorders. Combination drugs that impact multiple targets simultaneously are better at controlling complex disease systems, are less prone to drug resistance and are the standard of care in many important therapeutic areas. The combination drugs currently employed are primarily of rational design, but the increased efficacy they provide justifies in vitro discovery efforts for identifying novel multi-target mechanisms. In this review, we discuss the biological rationale for combination therapeutics, review some existing combination drugs and present a systematic approach to identify interactions between molecular pathways that could be leveraged for therapeutic benefit.

Drug Combinations↗

PubMed1980

Three-receptor, clonal expansion model for selection of self-recognition in the thymus.

The postulate is made that dual recognition by T lymphocytes is due to two types of receptor, one encoded by antibody genes and one by a distinct multigene family with simple rules for expression. This postulate leads to a model explaining ontogenic and evolutionary selection for self recognition, T lymphocyte effector function, the apparent high frequency of alloreactive T cells and immune response gene activity. The model is contrasted with previous explanations of self-recognition phenomena.

Animals↗

PubMed1978

[Genetic factors in the etiology of breast cancer (author's transl)].

A review of literature shows that, at present, genetic factors are difficult to distinguish from environmental factors. A number of studies have put into light relationships between factors tranmetted genetically and an increased risk of breast cancer in some women. This might be a reflect of the transmission of a certain susceptibility. However, one of these factors alone cannot explain the increase of the risk. Most likely, as for many types of cancers, the development of breast cancer is due both to a multigenic transmission of a certain susceptibility and to the action of environmental factors. Though, epidemiological studies make possible to identify a high risk population. A regular follow-up of this population would permit early diagnosis and possibly prophylactic measures concerning the known environmental factors, and in particular hormonal factors.

Adult↗

PubMed1984

A glyceraldehyde-3-phosphate dehydrogenase pseudogene on the short arm of the human X chromosomes defines a multigene family.

A human X chromosome-derived gene sequence which recognises an abundant, 1.2-kb mRNA in several cell types was previously isolated during a study to identify expressed sequences from an X chromosome recombinant library. Further characterisation of this clone, acronym OA1, has shown that it maps to the short arm of the X, at Xp21 to Xp22. A 777-bp fragment of the clone which hybridizes to the 1.2-kb mRNA has been sequenced, and the inferred amino acid sequence shows 80% homology with the published protein sequence for human muscle glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The fragment shows even higher homology (87%) with pig muscle GAPDH. The OA1 clone selects an mRNA which translates in vitro into a polypeptide of 36 K, the subunit size of GAPDH. However, the X-sequence is most probably a pseudogene whose structure is consistent with it having arisen by reverse transcription of a GAPDH or GAPDH-related mRNA followed by insertion into the X chromosome. The GAPDH-related portion of OA1 hybridizes to several DNA fragments in human and mouse DNA, and six fibroblast cDNA clones which cross-hybridize to OA1 identify the same genomic fragments as OA1. This series of clones identifies a new, conserved GAPDH-related multigene family.

Amino Acid Sequence↗

PubMed2005

Up-regulation of angiopoietin-2, matrix metalloprotease-2, membrane type 1 metalloprotease, and laminin 5 gamma 2 correlates with the invasiveness of human glioma.

Diffuse infiltration of malignant human glioma cells into surrounding brain structures occurs through the activation of multigenic programs. We recently showed that angiopoietin-2 (Ang2) induces glioma invasion through the activation of matrix metalloprotease-2 (MMP-2). Here, we report that up-regulation of Ang2, MMP-2, membrane type 1-MMP (MT1-MMP), and laminin 5 gamma 2 (LN 5 gamma 2) in tumor cells correlates with glioma invasion. Analyses of 57 clinical human glioma biopsies of World Health Organization grade I to IV tumors displaying a distinct invasive edge and 39 glioma specimens that only contain the central region of the tumor showed that Ang2, MMP-2, MT1-MMP, and LN 5 gamma 2 were co-overexpressed in invasive areas but not in the central regions of the glioma tissues. Statistical analyses revealed a significant link between the preferential expression of these molecules and invasiveness. Protein analyses of microdissected primary glioma tissue showed up-regulation and activation of MT1-MMP and LN 5 gamma 2 at the invasive edge of the tumors, supporting this observation. Concordantly, in human U87MG glioma xenografts engineered to express Ang2, increased expression of MT1-MMP and LN 5 gamma 2, along with MMP-2 up-regulation, in actively invading glioma cells was also evident. In cell culture, stimulation of glioma cells by overexpressing Ang2 or exposure to exogenous Ang2 promoted the expression and activation of MMP-2, MT1-MMP, and LN 5 gamma 2. These results suggest that up-regulation of Ang2, MMP-2, MT1-MMP, and LN 5 gamma 2 is associated with the invasiveness displayed by human gliomas and that induction of these molecules by Ang2 may be essential for glioma invasion.

Angiopoietin-2↗

PubMed2006

Plant methionine sulfoxide reductase A and B multigenic families.

Methionine oxidation to methionine sulfoxide (MetSo), which results in modification of activity and conformation for many proteins, is reversed by an enzyme present in most organisms and termed as methionine sulfoxide reductase (MSR). On the basis of substrate stereospecificity, two types of MSR, A and B, that do not share any sequence similarity, have been identified. In the present review, we first compare the multigenic MSR families in the three plant species for which the genome is fully sequenced: Arabidopsis thaliana, Oryza sativa, and Populus trichocarpa. The MSR gene content is larger in A. thaliana (five MSRAs and nine MSRBs) compared to P. trichocarpa (five MSRAs and four MSRBs) and O. sativa (four MSRAs and three MSRBs). A complete classification based on gene structure, sequence identity, position of conserved reactive cysteines and predicted subcellular localization is proposed. On the basis of in silico and experimental data originating mainly from Arabidopsis, we report that some MSR genes display organ-specific expression patterns and that those encoding plastidic MSRs are highly expressed in photosynthetic organs. We also show that the expression of numerous MSR genes is enhanced by environmental conditions known to generate oxidative stress. Thioredoxins (TRXs) constitute very likely physiological electron donors to plant MSR proteins for the catalysis of MetSO reduction, but the specificity between the numerous TRXs and methionine sulfoxide reductases (MSRs) present in plants remains to be investigated. The essential role of plant MSRs in protection against oxidative damage has been recently demonstrated on transgenic Arabidopsis plants modified in the content of cytosolic or plastidic MSRA.

Methionine Sulfoxide Reductases↗

PubMed2002

Phospholipases C are involved in the virulence of Mycobacterium tuberculosis.

Phospholipases C play a role in the pathogenesis of several bacteria. Mycobacterium tuberculosis, the causative agent of tuberculosis, possesses four genes encoding putative phospholipases C, plcA, plcB, plcC and plcD. However, the contribution of these genes to virulence is unknown. We constructed four single mutants of M. tuberculosis each inactivated in one of the plc genes, a triple plcABC mutant and a quadruple plcABCD mutant. The mutants all exhibited a lower phospholipase C activity than the wild-type parent strain, demonstrating that the four plc genes encode a functional phospholipase C in M. tuberculosis. Functional complementation of the Delta plcABC triple mutant with the individual plcA, plcB and plcC genes restored in each case about 20% of the total Plc activity detected in the parental strain, suggesting that the three enzymes contribute equally to the overall Plc activity of M. tuberculosis. RT-PCR analysis of the plc genes transcripts showed that the expression of these genes is strongly upregulated during the first 24 h of macrophage infection. Moreover, the growth kinetics of the triple and quadruple mutants in a mouse model of infection revealed that both mutants are attenuated in the late phase of the infection emphasizing the importance of phospholipases C in the virulence of the tubercle bacillus.

Animals↗

PubMed2000

Intercellular communication in the eye: clarifying the need for connexin diversity.

In the vertebrate eye, virtually every cell type is directly coupled to its neighbors by intercellular channels present in gap junctions. Although these structures share the common property of allowing adjacent cells to directly exchange ions, second messengers and small metabolites, intercellular channels in the eye also play a specific role in distinct functions such as neuronal transmission at electrotonic synapses in the retina, and the maintenance of homeostasis in the avascular lens. The structural proteins comprising these channels, the connexins (Cx), are a multigene family of which many members are expressed in the eye, even in the same cell type. This molecular heterogeneity poses the crucial question of whether and how a diversity in gap junctional structural proteins influences intercellular communication in ocular tissues. This review will focus on two recent advances in the understanding of connexin diversity in regard to the eye. First, connexin knockouts have demonstrated that postnatal development and homeostasis in the lens requires multiple connexin proteins. Secondly, functional characterization of new connexins that are abundantly expressed in the retina has revealed biophysical properties that mimic those recorded from retinal neurons.

Animals↗

PubMed1995

Transgenic analysis of a hybrid poplar wound-inducible promoter reveals developmental patterns of expression similar to that of storage protein genes.

The wound-inducible win3 multigene family from hybrid poplars (Populus trichocarpa x Populus deltoides) encodes proteins with structural similarities with Kunitz-type protease inhibitors (H.D. Bradshaw Jr., J.B. Hollick, T.J. Parsons, H.R.G. Clarke, M.P. Gordon [1990] Plant Mol Biol 14: 51-59), and at least one member, win3.12, is transcribed de novo in the injured and uninjured leaves of wounded trees (J.B. Hollick, M.P. Gordon [1993] Plant Mol Biol 22: 561-572). A previous study demonstrated that 1352 bp of 5' flanking DNA from the win3.12 gene confers local wound-regulated expression of the beta-glucuronidase gene in transgenic tobacco (Nicotiana tabacum cv Xanthi n.c.) (J.B. Hollick, M.P. Gordon [1993] Plant Mol Biol 22: 561-572). We extend this transgenic analysis here by examining the developmental regulation and systemic wound induction conferred by the same transgene construct in tobacco. Biochemical and histochemical surveys of beta-glucuronidase activity are described for four, independent transgenic lines. The observed spatial and temporal expression patterns coincide with dormant storage tissues and with previously described expression patterns for both seed and vegetative storage protein genes. Developmental northern blot analysis of win3 RNA levels in poplar seeds confirms that proper temporal expression of the reporter gene is maintained during tobacco seed maturation. These results demonstrate that a putative Kunitz-type protease inhibitor can be wound inducible in addition to being expressed in developing seeds.

Gene Expression Regulation, Developmental↗

PubMed2002

Sequence analysis of the ly49 cluster in C57BL/6 mice: a rapidly evolving multigene family in the immune system.

The cytotoxic activity of murine natural killer cells is controlled in part through the action of genes belonging to the Ly49 family. Members of this multigene family are found in a region on mouse chromosome 6 termed the natural killer gene complex. Using data available through public databases, we performed sequence analysis of a 620-kb region in C57Bl/6 (B6) mice that contains the Ly49 genes. The contiguous genomic sequence has allowed us to describe the complete B6 Ly49 gene repertoire, which includes two recently described genes as well as three partial genes. We have shown that the genes in the cluster have evolved through a series of large duplication events involving units of one or more genes and we have attempted to characterize the nature of the duplication end points. Finally, we have used information regarding gene sequence relationships and insertion of repetitive elements to construct a model for the evolution of the gene cluster. Our study illustrates that the Ly49 cluster represents an example of a rapidly evolving gene family, and continued analysis of this region in other strains will undoubtedly provide further insight into mechanisms for generating genomic diversity.

Animals↗

PubMed1989

Ly-6: a multigene family in search of a function.

Differentiation antigens can be simply defined as cell surface antigens that distinguish one cell type from another. The Ly-6 family of cell surface antigens might easily be regarded as a prototype for the analysis of the function of differentiation antigens on immunocompetent cells. Although a number of studies with antisera, in the late 1970s, established that the Ly-6 antigens exhibit an unusual pattern of expression on T and B lymphocytes, functional studies failed to demonstrate that the expression of Ly-6 defines a unique subpopulation of immunocompetent cells. Paradoxically, the development of anti-Ly-6 monoclonal antibodies led to a further decline in interest in this group of antigens, as the complexity of the results relegated Ly-6 to the realm of the die-hard immunogeneticist. Over the past five years, interest in Ly-6 has been rekindled and in this review Ethan Shevach and Patricia Korty summarize recent studies on the serology, biochemical and molecular structure, and the function of the products of this multigene family.

Amino Acid Sequence↗

PubMed1990

The Arabidopsis thaliana plasma membrane H(+)-ATPase multigene family. Genomic sequence and expression of a third isoform.

The plasma membrane of higher plants contains a H(+)-ATPase as its major ion pump. This enzyme belongs to the P-type family of cation-translocating enzymes and generates the proton-motive force that drives solute uptake across the plasma membrane. In Arabidopsis thaliana the plasma membrane H(+)-ATPase is encoded by a multigene family (Harper, J. F., Surowy, T. K., and Sussman, M. R. (1989) Proc. Natl. Acad. Sci. U. S. A. 86, 1234-1238). The complete genomic sequence of a third Arabidopsis H(+)-ATPase isoform (referred to as AHA2) is presented here, and the predicted protein sequence is compared with previously published AHA1, AHA3, and tobacco Nicotiana plumbaginifolia NP1 isoforms. The AHA2 gene is most similar to AHA1, with predicted proteins containing 95% amino acid identity. The mRNA start site and 5'-untranslated sequence for AHA2 were determined from cDNA amplified by the polymerase chain reaction. The 5' region contains a 23-base pair (bp) polypyrimidine sequence and a short upstream reading frame. In comparison with the 16 introns reported in AHA3, AHA2 is missing one intron in the 5'-untranslated region and a second intron in the C-terminal coding region. An unusually large intron for Arabidopsis (greater than 1000 bp) is present at the beginning of the coding sequence of both AHA2 and AHA3. In the 3'-untranslated sequence of AHA1 and AHA2 but not AHA3, there is a 65-bp region of 85% identity and a second shorter region of 16-bp identity harboring an unusual putative poly(A) addition signal (dTTTGAAGAAACAAGGC). Northern blot analysis indicates that AHA2 mRNA relative to total cellular RNA is expressed at significantly higher levels in root tissue as compared with shoot tissue.

Amino Acid Sequence↗

PubMed1999

Mouse NKR-P1B, a novel NK1.1 antigen with inhibitory function.

The mouse NK1.1 Ag originally defined as NK cell receptor (NKR)-P1C (CD161) mediates NK cell activation. Here, we show that another member of the mouse CD161 family, NKR-P1B, represents a novel NK1.1 Ag. In contrast to NKR-P1C, which functions as an activating receptor, NKR-P1B inhibits NK cell activation. Association of NKR-P1B with Src homology 2-containing protein tyrosine phosphatase-1 provides a molecular mechanism for this inhibition. The existence of these two NK1.1 Ags with opposite functions suggests a potential role for NKR-P1 molecules, such as those of the Ly-49 gene family, in regulating NK cell function.

Amino Acid Sequence↗