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PubMed1975

Comparative analyses of members of the Venezuelan equine encephalomyelitis virus complex.

Polyacrylamide gel electrophoretic examination of viruses selected from the Venezuelan equine encephalomyelitis (VEE) complex revealed distinct strain to strain differences in profiles of the two virion envelope proteins. The core protein was identical in all viruses tested. We detected five electrophoretic patterns into which the virus strains could be classified and these were designated alpha (alpha), beta (beta), gamma (gamma), delta (delta), and episolon (episolon). Isolates representing variant E of subtype I exhibited a profile characterized by only one apparent envelope band. The epizootic subtypes I-A, I-B, I-C and the sylvatic subtype II viruses contained at least two envelope proteins which differed in molecular weight according to virus strain but which were not necessarily specific for antigenic variety. These results generally, though not uniformly, support the serologic classification of the VEE virus complex and suggested that the usefulness of the classification scheme could be complemented by the inclusion of biochemical criteria.

Animals↗
PubMed1982

Effect of anti-pilus antibodies on survival of gonococci within guinea pig subcutaneous chambers.

Guinea pigs were immunized with either alpha or beta pili from Neisseria gonorrhoeae P9 before the inoculation of subcutaneous chambers with a mixture of variants having alpha, beta, gamma, or delta pili. Animals immunized with alpha pili showed significant protection, but those immunized with beta pili did not. The degree of protection could be correlated with the cross-reactivity of the antibodies produced to the heterologous pilus types.

Animals↗
PubMed1997

Localization of BRCA1 and a splice variant identifies the nuclear localization signal.

Inherited mutations in BRCA1 confer susceptibility to breast and ovarian neoplasms. However, the function of BRCA1 and the role of BRCA1 in noninherited cancer remain unknown. Characterization of alternately spliced forms of BRCA1 may identify functional regions; thus, we constructed expression vectors of BRCA1 and a splice variant lacking exon 11, designated BRCA1 delta 672-4095. Immunofluorescence studies indicate nuclear localization of BRCA1 but cytoplasmic localization of BRCA1 delta 672-4095. Two putative nuclear localization signals (designated NLS1 and NLS2) were identified in exon 11; immunofluorescence studies indicate that only NLS1 is required for nuclear localization. RNA analysis indicates the expression of multiple, tissue-specific forms of BRCA1 RNAs; protein analysis with multiple antibodies suggests that at least three BRCA1 isoforms are expressed, including those lacking exon 11. The results suggest that BRCA1 is a nuclear protein and raise the possibility that splicing is one form of regulation of BRCA1 function by alteration of the subcellular localization of expressed proteins.

3T3 Cells↗
PubMed2025

Evolution of SARS-CoV-2 in white-tailed deer in Pennsylvania 2021-2024.

SARS-CoV-2 continues to transmit and evolve in humans and animals. White-tailed deer (Odocoileus virginianus) have been previously identified as a zoonotic reservoir for SARS-CoV-2 with high rates of infection and probable spillback into humans. Here we report sampling 1,127 white-tailed deer (WTD) in Pennsylvania, and a genomic analysis of viral dynamics spanning 1,017 days between April 2021 and January 2024. To assess viral load and genotypes, RNA was isolated from retropharyngeal lymph nodes and analyzed using RT-qPCR and viral whole genome sequencing. Samples showed a 14.64% positivity rate by RT-qPCR. Analysis showed no association of SARS-CoV-2 prevalence with age, sex, or diagnosis with Chronic Wasting Disease. From the 165 SARS-CoV-2 positive WTD, we recovered 25 whole genome sequences and an additional 17 spike-targeted amplicon sequences. The viral variants identified included 17 Alpha, 11 Delta, and 14 Omicron. Alpha largely stopped circulating in humans around September 2021, but persisted in WTD as recently as March of 2023. Phylodynamic analysis of pooled genomic data from Pennsylvania documents at least 12 SARS-CoV-2 spillovers from humans into WTD, including a recent series of Omicron spillovers. Prevalence was higher in WTD in regions with crop coverage rather than forest, suggesting an association with proximity to humans. Analysis of seasonality showed increased prevalence in winter and spring. Multiple examples of recurrent mutations were identified associated with transmissions, suggesting WTD-specific evolutionary pressures. These data document ongoing infections in white-tailed deer, probable onward transmission in deer, and a remarkable rate of new spillovers from humans.

Animals↗
PubMed2003

A mutation in protein phosphatase type 2A as a cause of melanoma progression.

The BL6 subline was derived from the F10 line, which was derived from the B16 mouse melanoma cell line. BL6 cells are more invasive than F10 cells and differ genetically from F10 cells by an alteration of the gene encoding the B56gamma regulatory subunit of protein phosphatase 2A (PP2A). This alteration results in the transcription of mRNA encoding a truncated variant of the B56gamma1 isoform (Delta-gamma-1). Delta-gamma-1 is capable of targeting PP2A to the specific subcellular sites but incapable of promoting the dephosphorylation of specific substrates that is normally mediated by the B56gamma subunit-containing PP2A holoenzyme. It thus appears that activities of this type of holoenzymes decrease in cells expressing Delta-gamma-1. Recently, we found two possible ways how Delta-gamma-1 contributes to the enhanced metastatic potential of BL6 cells. The two ways seemed far away from each other: Delta-gamma-1 influenced both the nuclear and cytoplasmic functions of the cell. In the cytoplasm, Delta-gamma-1 localized at the Golgi complex and accelerated Golgi-mediated vesicle transport. On the other hand, Delta-gamma-1 disturbed the cell-cycle regulation. In response to gamma-irradiation, protein levels of Delta-gamma-1 were markedly increased in BL6 cells. Subsequently the integrity of cell-cycle checkpoint became more aberrant in BL6 cells than that in F10 cells. These two actions of Delta-gamma-1 could results in the enhancement of the malignant phenotypes of melanoma cells, as discussed in this review.

Animals↗
PubMed2000

Glycoprotein 130 and c-kit signals synergistically induce thrombopoietin production by hematopoietic cells.

We have reported that simultaneous activation of glycoprotein (gp) 130 and c-kit signals by interleukin (IL)-6, soluble IL-6 receptor (sIL-6R), and stem cell factor (SCF) promotes proliferation of human hematopoietic progenitor cells and their differentiation into erythroid, myelocytic, and megakaryocytic cells. We recently found that erythropoietin produced by erythroid progenitors stimulates erythropoiesis via gp130 and c-kit signals. Here we examined thrombopoietin (TPO) production by hematopoietic cells cultured with IL-6, sIL-6R, and SCF. Reverse transcription-polymerase chain reaction analysis indicated that hematopoietic cells generated from cord blood CD34+ cells with the 3 factors expressed a minor splice variant of TPO messenger RNA, P1 delta E2, which can be translated to TPO protein more efficiently than regularly spliced isoforms. The reduction in c-mpl, receptors for TPO, by antisense oligodeoxynucleotides suppressed the generation of erythroid, myelocytic, and pluripotent progenitors in suspension culture, plus colony formation of megakaryocytic progenitors in addition to these progenitors in clonal culture of cord blood CD34+ cells with IL-6, sIL-6R, and SCF. The addition of anti-human TPO antibody to the clonal culture also suppressed colony formation. These findings indicate that TPO production by hematopoietic cells stimulated by IL-6, sIL-6R, and SCF is involved in promoting their own growth.

Antigens, CD↗
PubMed1983

Restriction endonuclease mapping of gamma-delta-beta-globin region in G gamma (beta)+ HPFH and a Chinese A gamma HPFH variant.

Restriction endonuclease mapping of the beta-globin genomic region was used for studying the molecular basis of two variants of hereditary persistence of fetal hemoglobin (HPFH): an African G gamma (beta)+ HPFH and a Chinese HPFH variant with predominant synthesis of A gamma chains. HPFH and control DNA samples were digested with a battery of restriction enzymes, and the fragments were identified by hybridization to a family of discrete probes. DNA fragments from the A gamma HPFH (Chinese) and the G gamma (beta)+ HPFH individuals were identical with those of the normal controls. These findings suggest that the two mutants are the result of small structural anomalies of DNA sequences that play a role in the regulation of the expression of gamma-globin genes.

Chromosome Mapping↗
PubMed1993

Direct measurements of in situ interactions of rat brain opioid receptors with the guanine nucleotide-binding protein Go.

The interactions of rat brain cortical opioid receptors with the guanine nucleotide-binding protein (G protein) Go were probed in membranes by examining the ability of selective antipeptide anti-G protein antisera to disrupt receptor-G protein interactions. This was measured both by antibody-induced alterations in the characteristics of agonist binding to mu and delta receptor binding sites and by antibody attenuation of opioid stimulation of high affinity GTPase activity. Antisera to the amino-terminal 16 amino acids (ON1), amino acids 22-35 (IM1), and the carboxyl-terminal decapeptide (OC2) of forms of Go alpha were able to selectively immunoprecipitate Go from rat cortical membranes. Both antisera OC2 and ON1 were able to immunoprecipitate Go alpha quantitatively. Preincubation of rat cortical membranes with an IgG fraction isolated from antiserum OC2 was able to produce a marked reduction in the ability of the synthetic enkephalin [D-Ala2,D-Leu5] enkephalin (DADLE) (which interacts with delta and mu but not significantly with kappa receptors) to displace specific binding of [3H] diprenorphine (which binds to all of these sites), demonstrating a clear interaction of the mu and delta receptors with one or more variants of Go. An IgG fraction from antiserum ON1 was able to mimic this effect, suggesting that the amino-terminal region of G protein alpha subunits also plays a role in receptor-G protein interactions. In contrast, an IgG fraction from antiserum IM1 was unable to alter the characteristics of DADLE displacement of [3H] diprenorphine binding. Similarly, an antiserum (SG1) directed against the carboxyl-terminal decapeptide common to the alpha subunits of Gi1 and Gi2 was unable to reduce the affinity of DADLE binding to opioid receptors. Use of antiserum OC2 in experiments that allowed pharmacological examination of only the mu-opioid receptor provided independent evidence for the interaction of this receptor site with Go.

Amino Acid Sequence↗
PubMed1994

Ultrastructural localization of variant forms of cystic fibrosis transmembrane conductance regulator in human bronchial epithelial of xenografts.

Cystic fibrosis (CF) is caused by mutations in the gene encoding a cyclic adenosine monophosphate (cAMP)-regulated chloride (CI) channel called the CF transmembrane conductance regulator (CFTR). Previous in vitro studies have indicated that the most common mutation, delta F508 CFTR (a deletion of phenylalanine 508), encodes a protein that is trapped in the endoplasmic reticulum (ER), leading to loss of cAMP-regulated CI transport at the plasma membrane. Another common variant, G551D CFTR (a G-->D missense mutation at position 551), is properly transported to the plasma membrane but is unresponsive to cAMP. These hypotheses are based primarily on studies in culture cells. We have attempted to extend the in vitro experiments by characterizing the molecular pathogenesis of the common mutations, delta F508 and G551D, in the context of a more relevant setting, the pseudostratified epithelium of a proximal human airway. Recombinant adenoviruses were used to transduce normal and variant forms of CFTR into surface epithelial cells of human bronchial xenografts grown in nu/nu mice. Recombinant forms of CFTR RNA and protein were expressed at levels that exceed expression of the endogenous gene. Immunolocalization of CFTR at the light and electron microscopic level indicated that products of the wild type and G551D alleles are found primarily at the apical plasma membrane of ciliated cells, while the delta F508 variant is distributed diffusely throughout the ER. Our data support previous observations primarily made in vitro that the G551D variant is a dysfunctional channel that is properly processed and that the delta F508 variant undergoes biosynthetic arrest at the level of the ER.

Adenoviridae↗
PubMed2001

The protein tyrosine phosphatase TCPTP suppresses the tumorigenicity of glioblastoma cells expressing a mutant epidermal growth factor receptor.

Glioblastoma multiforme (GBM) is the most aggressive type of glioma and GBMs frequently contain amplifications or mutations of the EGFR gene. The most common mutation results in a truncated receptor tyrosine kinase known as Delta EGFR that signals constitutively and promotes GBM growth. Here, we report that the 45-kDa variant of the protein tyrosine phosphatase TCPTP (TC45) can recognize Delta EGFR as a cellular substrate. TC45 dephosphorylated Delta EGFR in U87MG glioblastoma cells and inhibited mitogen-activated protein kinase ERK2 and phosphatidylinositol 3-kinase signaling. In contrast, the substrate-trapping TC45-D182A mutant, which is capable of forming stable complexes with TC45 substrates, suppressed the activation of ERK2 but not phosphatidylinositol 3-kinase. TC45 inhibited the proliferation and anchorage-independent growth of Delta EGFR cells but TC45-D182A only inhibited cellular proliferation. Notably, neither TC45 nor TC45-D182A inhibited the proliferation of U87MG cells that did not express Delta EGFR. Delta EGFR activity was necessary for the activation of ERK2, and pharmacological inhibition of ERK2 inhibited the proliferation of Delta EGFR-expressing U87MG cells. Expression of either TC45 or TC45-D182A also suppressed the growth of Delta EGFR-expressing U87MG cells in vivo and prolonged the survival of mice implanted intracerebrally with these tumor cells. These results indicate that TC45 can inhibit the Delta EGFR-mediated activation of ERK2 and suppress the tumorigenicity of Delta EGFR-expressing glioblastoma cells in vivo.

Animals↗
PubMed2000

Human-Saccharomyces cerevisiae proliferating cell nuclear antigen hybrids: oligomeric structure and functional characterization using in vitro DNA replication.

The proliferating cell nuclear antigen (PCNA) is a highly conserved protein required for the assembly of the DNA polymerase delta (pol delta) holoenzyme. Because PCNAs from Saccharomyces cerevisiae and human do not complement each other using in vitro or in vivo assays, hybrids of the two proteins would help identify region(s) involved in the assembly of the pol delta holoenzyme. Two mutants of human PCNA, HU1 (D21E) and HU3 (D120E), and six hybrids of human and S. cerevisiae PCNA, HC1, HC5, CH2, CH3, CH4, and CH5, were prepared by swapping corresponding regions between the two proteins. In solution, all PCNA assembled into trimers, albeit to different extents. These PCNA variants were tested for stimulation of pol delta and in vitro replication of M13 and SV40 DNA as well as to stimulate the ATPase activity of replication factor C (RF-C). Our data suggest that in addition to the interdomain connecting loop and C terminus, an additional site in the N terminus is required for pol delta interaction. PCNA mutants and hybrids that stimulated pol delta and RF-C were deficient in M13 and SV40 DNA replication assays, indicating that PCNA-induced pol delta stimulation and RF-C-mediated loading are not sufficient for coordinated DNA synthesis at a replication fork.

Adenosine Triphosphatases↗
PubMed1981

Switch from hapten-specific immunoglobulin M to immunoglobulin D secretion in a hybrid mouse cell line.

From a hybrid mouse cell line (B1-8) that secreted an IgM, lambda 1 anti-(4-hydroxy-3-nitrophenyl)acetyl antibody but that had no detectable surface IgM, selection for a variant with lambda 1 chains on the surface resulted in the isolation of a line that had switched from mu to delta expression. The surface and secreted Igs of this line were typed as IgD with two monoclonal antibodies, and the parental IgM and variant IgD molecules carried the same variable regions as judged by hapten-binding and idiotypic analysis. The surface and secreted delta chains of the IgD variant have apparent molecular weights of 64,000 and 61,000, respectively. However, the unglycosylated secreted delta polypeptide chain has a molecular weight of only 44,000. The secreted IgD exists predominantly in the delta 2 lambda A2 form, does not contain J protein, is relatively stable in serum, and does not fix complement.

Animals↗
PubMed2001

Genotypes and polymorphisms of mutant CCR5-delta 32, CCR2-64I and SDF1-3' a HIV-1 resistance alleles in indigenous Han Chinese.

OBJECTIVE: To evaluate the frequencies and polymorphisms of CCR5-delta 32, CCR2-64I and SDF1-3' A alleles conferring resistance to HIV-1 infection in Chinese population from Han ethnic origin. METHODS: This cohort was comprised of 1251 subjects (915 men and 336 women) aged 15-80 years and none was HIV-1 positive. Genotyping of allelic CCR5-delta 32, CCR2-64I and SDF1-3' A variants was performed using PCR or PCR/RFLP assay, and further confirmed by direct DNA sequencing. RESULTS: Our finding shows that the delta 32 deletion mutation in the CCR5 gene does occur in this population and can be inherited in a Mendelian fashion in indigenous Han Chinese at a very low frequency of 0.00119 (n = 1254). The frequencies of mutant CCR2-64I and SDF1-3' A alleles were 0.20023 (n = 1251) and 0.2873 (n = 893), in this population, which are higher than those found in American Caucasians. Furthermore the polymorphisms of CCR2-64I and SDF1-3' A alleles in the Han Chinese population were different from those in American Caucasians. Statistical analysis showed that the genotype distribution of CCR5-delta 32, CCR2-64I and SDF1-3' A alleles was in equilibrium according to the Hardy-Weinberg equation. CONCLUSION: The CCR5-delta 32 mutation may not be a major resistant factor against HIV-1 infection in indigenous Han Chinese. The significance of higher frequencies of CCR2-641 and SDF1-3' A alleles (0.20023 and 0.2791) in the Han population remains to be clarified in HIV-1-positive carriers and AIDS patients.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Expression of alternatively spliced estrogen receptor alpha mRNAs is increased in breast cancer tissues.

We previously identified 20 different alternatively spliced estrogen receptor alpha (ERalpha) mRNAs that have deletions in various combinations of exons in breast cancer cell lines using a novel 'Splice Targeted Approach' [J. Steroid Biochem. Mol. Biol. 72 (2000) 249]. In the current study, we compared the frequency of alternatively spliced ERalpha variant expression in 35 reduction mammoplasty and 38 breast cancer tissues with known ERalpha, ERbeta status using this highly specific 'Splice Targeted Approach'. A total of 16 different alternatively spliced variants were identified that have deletions in various combinations of exons in normal, as well as cancer tissues. However, not all 16 variants were present in every tissue. The frequency and type of variants in normal and cancer tissues was significantly different. Majority of normal tissues expressed only single exon deletion variants with the exception of those in combination with exon 2Delta and 7Delta. Tumor tissues, on the other hand, showed increased frequency of multiple exon deletion mRNAs (P<0.019). In addition, cancer tissues also showed an increased frequency of all variants compared with normal tissues (P<0.044). Among the 16 variants, the dominant negative variant, exon 3Delta, showed the most significant increase in cancer tissues (P=0.000032). Specifically, we detected four different mRNAs that have exon 2 deletion-exon 2Delta; 2 and 4Delta; 2 and 5Delta; and 2, 4-5Delta in various combinations in both normal and cancer tissues. A large number of normal tissues expressed two transcripts-exon 2Delta and 2, 4-5Delta. The multiple exon deletion 2, 4-5Delta were predominant in cancer tissues. Only the single exon 3 deletion variant, exon 3Delta, was detected in normal tissues. Cancer tissues showed the presence of a double exon deletion variant, exons 3 and 7Delta, in addition to exon 3Delta. A small fraction of normal tissues showed exons 2-3Delta mRNAs, whereas, cancer tissues showed increased frequency of exons 2-3Delta expression in addition to a triple exon deletion variant, exons 2-3, and 5Delta. The expression of exon 4Delta; or 4 and 7Delta or both was equivalent in normal and cancer tissues. Exon 5Delta transcripts were present at very low levels in both normal and tumor tissues. A small percentage of cancer tissues but not normal tissues showed exon 6Delta mRNA. The presence of single, double, triple and quadruple exon deletion mRNAs, exon 7Delta; 7 and 4Delta; 7, 3-4Delta; 7, 3-5Delta, respectively, were detected in normal as well as cancer tissues. Each normal and cancer tissue had a distinct profile of ERalpha wild type, ERbeta wild type and ERalpha splice variants. Heterogeneity in ER isoform profiles may result in variations in estrogen/anti-estrogen binding and activation/inactivation of estrogen-dependent genes, and, therefore, may have implications in the risk of developing breast cancer, survival with the disease and response to anti-estrogen, as well as other therapies.

Alternative Splicing↗
PubMed1998

Structure and stability of the P93G variant of ribonuclease A.

The peptide bonds preceding Pro 93 and Pro 114 of bovine pancreatic ribonuclease A (RNase A) are in the cis conformation. The trans-to-cis isomerization of these bonds had been indicted as the slow step during protein folding. Here, site-directed mutagenesis was used to replace Pro 93 or Pro 114 with a glycine residue, and the crystalline structure of the P93G variant was determined by X-ray diffraction analysis to a resolution of 1.7 A. This structure is essentially identical to that of the wild-type protein, except for the 91-94 beta-turn containing the substitution. In the wild-type protein, the beta-turn is of type VIa. In the P93G variant, this turn is of type II with the peptide bond preceding Gly 93 being trans. The thermal stabilities of the P93G and P114G variants were assessed by differential scanning calorimetry and thermal denaturation experiments monitored by ultraviolet spectroscopy. The value of delta deltaGm which reports on the stability lost in the variants, is 1.5-fold greater for the P114G variant than for the P93G variant. The greater stability of the P93G variant is likely due to the relatively facile accommodation of residues 91-94 in a type II turn, which has a preference for a glycine residue in its i + 2 position.

Amino Acid Substitution↗
PubMed1999

Downregulation of delta CaM kinase II in human tumor cells.

Over two dozen alternative splice variants of CaMK-II, the type II Ca(2+)/CaM-dependent protein kinase, are encoded from four genes (alpha, beta, gamma and delta) in mammalian cells. Isozymes of alpha and beta CaMK-II are well characterized in brain; however, an understanding of the relative endogenous levels of CaMK-II isozymes in a wide variety of non-neuronal cells has not yet been described. In this study, we have demonstrated that CaMK-II consists primarily of the 54 kDa delta CaMK-II (delta(2) or delta(C)) isozyme in rodent fibroblasts. beta and gamma CaMK-II isozymes are minor and alpha CaMK-II was not expressed. The primary delta CaMK-II in human fibroblasts and the MCF10A mammary epithelial cell line was the 52 kDa delta(4) CaMK-II, an isozyme identical to delta(2) except for a missing 21-amino-acid C-terminal tail. delta CaMK-II levels were diminished in both human and rodent fibroblasts after SV40 transformation and in the mammary adenocarcinoma MCF7 cell line when compared to MCF10A cells. In fact, most tumor cells exhibited CaMK-II specific activities which were two- to tenfold lower than in untransformed fibroblasts. We conducted complementary CaMK-II studies on the NGF-induced differentiation of rat PC-12 cells. Although no new synthesis of CaMK-II occurs, neurite outgrowth in these cells is accompanied by a preferential activation of delta CaMK-II. Endogenous delta CaMK-II has a perinuclear distribution in fibroblasts and extends along neurites in PC-12 cells. These findings point to a role for delta CaMK-II isozymes in cellular differentiation.

3T3 Cells↗
PubMed2002

Organization of the multifunctional enzyme type 1: interaction between N- and C-terminal domains is required for the hydratase-1/isomerase activity.

Rat peroxisomal multifunctional enzyme type 1 (perMFE-1) is a monomeric protein of beta-oxidation. We have defined five functional domains (A, B, C, D and E) in the perMFE-1 based on comparison of the amino acid sequence with homologous proteins from databases and structural data of the hydratase-1/isomerases (H1/I) and (3 S )-hydroxyacyl-CoA dehydrogenases (HAD). Domain A (residues 1-190) comprises the H1/I fold and catalyses both 2-enoyl-CoA hydratase-1 and Delta(3)-Delta(2)-enoyl-CoA isomerase reactions. Domain B (residues 191-280) links domain A to the (3 S )-dehydrogenase region, which includes both domain C (residues 281-474) and domain D (residues 480-583). Domains C and D carry features of the dinucleotide-binding and the dimerization domains of monofunctional HADs respectively. Domain E (residues 584-722) has sequence similarity to domain D of the perMFE-1, which suggests that it has evolved via partial gene duplication. Experiments with engineered perMFE-1 variants demonstrate that the H1/I competence of domain A requires stabilizing interactions with domains D and E. The variant His-perMFE (residues 288-479)Delta, in which the domain C is deleted, is stable and has hydratase-1 activity. It is proposed that the extreme C-terminal domain E in perMFE-1 serves the following three functions: (i) participation in the folding of the N-terminus into a functionally competent H1/I fold, (ii) stabilization of the dehydrogenation domains by interaction with the domain D and (iii) the targeting of the perMFE-1 to peroxisomes via its C-terminal tripeptide.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2005

Mouse glucose transporter 9 splice variants are expressed in adult liver and kidney and are up-regulated in diabetes.

A novel glucose transporter (GLUT), mouse GLUT9 (mGLUT9), was recently cloned from mouse 7-d embryonic cDNA. Several splice variants of mGLUT9 were described, two of which were cloned (mGLUT9a and mGLUT9a Delta 209-316). This study describes the cloning and characterization of another splice variant, mGLUT9b. Cloned from adult liver, mGLUT9b is identical to mGLUT9a except at the amino terminus. Based on analysis of the genomic structure, the different amino termini result from alternative transcriptional/translational start sites. Expression and localization of these two mGLUT9 splice variants were examined in control and diabetic adult mouse tissues and in cell lines. RT-PCR analysis demonstrated expression of mGLUT9a in several tissues whereas mGLUT9b was observed primarily in liver and kidney. Using a mGLUT9-specific antibody, Western blot analysis of total membrane fractions from liver and kidney detected a single, wide band, migrating at approximately 55 kDa. This band shifted to a lower molecular mass when deglycosylated with peptide-N-glycosidase F. Both forms were present in liver and kidney. Immunohistochemical localization demonstrated basolateral distribution of mGLUT9 in liver hepatocytes and the expression of mGLUT9 in specific tubules in the outer cortex of the kidney. To investigate the alternative amino termini, mGLUT9a and mGLUT9b were overexpressed in kidney epithelium cell lines. Subcellular fractions localized both forms to the plasma membrane. Immunofluorescent staining of polarized Madin Darby canine kidney cells overexpressing mGLUT9 depicted a basolateral distribution for both splice variants. Finally, mGLUT9 protein expression was significantly increased in the kidney and liver from streptozotocin-induced diabetic mice compared with nondiabetic animals.

Age Factors↗