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PubMed1999

Fasting and leptin modulate adipose and muscle uncoupling protein: divergent effects between messenger ribonucleic acid and protein expression.

Leptin is believed to act through hypothalamic centers to decrease appetite and increase energy utilization, in part through enhanced thermogenesis. In this study, we examined the effects of fasting for 2 days and exogenous s.c. leptin, 200 microg every 8 h for 2 days, on the regulation of uncoupling protein (UCP) subtypes in brown adipose tissue (BAT) and gastrocnemius muscle. Northern blot analysis (UCP-1) and ribonuclease protection (UCP-2 and 3) were used for quantitative messenger RNA (mRNA) analysis, and specific antibodies were used to measure UCP-1 and UCP-3 total protein expression. Leptin, compared with vehicle, did not alter BAT UCP-1 or UCP-3 mRNA or protein expression when administered to normal ad libitum fed rats. Fasting significantly decreased BAT UCP-1 and UCP-3 mRNA expression, to 31% and 30% of ad libitum fed controls, respectively, effects which were prevented by administration of leptin to fasted rats. Fasting also significantly decreased BAT UCP-1 protein expression, to 67% of control; however, that effect was not prevented by leptin treatment. Fasting also decreased BAT UCP-3 protein, to 85% of control, an effect that was not statistically significant. Fasting, with or without leptin administration, did not affect BAT UCP-2 mRNA; however, leptin administration to ad libitum fed rats significantly increased BAT UCP-2 mRNA, to 138% of control. Fasting significantly enhanced gastrocnemius muscle UCP-3 mRNA (411% of control) and protein expression (168% of control), whereas leptin administration to fasted rats did not alter either of these effects. In summary, UCP subtype mRNA and protein are regulated in tissue- and subtype-specific fashion by leptin and food restriction. Under certain conditions, the effects of these perturbations on UCP mRNA and protein are discordant.

Adipose Tissue↗
PubMed1995

Transforming growth factor-beta induces plasminogen activator inhibitor type-1 in cultured human orbital fibroblasts.

PURPOSE: The level of constitutive plasminogen activator inhibitor type-1 (PAI-1) expression in cultured human orbital fibroblasts is considerably lower than that found in dermal fibroblasts. This divergence in PAI-1 expression implies differences in the pericellular proteolytic environment and, therefore, in the turnover of extracellular matrix. In this article, the authors examine the effect of transforming growth factor-beta (TGF-beta) on PAI-1 expression in orbital fibroblasts. METHODS: Human orbital and dermal fibroblasts were grown in culture. Confluent monolayers were treated with TGF-beta. PAI-1 in the extracellular matrix was quantitated by radiolabeling the cultures and electrophoresing the cellular material on SDS-PAGE. Medium content was determined by immunoprecipitation of [35S]PAI-1 with a rabbit, anti-human, polyclonal antibody. PAI-1 mRNA was determined by Northern hybridization. RESULTS: TGF-beta increased PAI-1 levels in orbital fibroblasts in a dose-dependent manner, up to 35-fold. The induction was maximal after 16 hours of treatment. The increases in extracellular matrix PAI-1 paralleled those observed in the medium. The steady state levels of the mRNA encoding the protein were upregulated by TGF-beta up to 60-fold 8 hours after the addition of TGF-beta. The fractional increase in PAI-1 expression in orbital fibroblasts was consistently greater than that observed in dermal strains. CONCLUSIONS: Exposure to TGF-beta consistently induces PAI-1 expression in orbital fibroblasts, cells that do not express the polypeptide constitutively at high levels. The effects are mediated at the pretranslational level and involve the upregulation of PAI-1 mRNA. These results suggest that TGF-beta may exert a profound regulatory influence on the pericellular proteolytic environment in orbital connective tissue.

Blotting, Northern↗
PubMed2006

The evolving doublecortin (DCX) superfamily.

BACKGROUND: Doublecortin (DCX) domains serve as protein-interaction platforms. Mutations in members of this protein superfamily are linked to several genetic diseases. Mutations in the human DCX gene result in abnormal neuronal migration, epilepsy, and mental retardation; mutations in RP1 are associated with a form of inherited blindness, and DCDC2 has been associated with dyslectic reading disabilities. RESULTS: The DCX-repeat gene family is composed of eleven paralogs in human and in mouse. Its evolution was followed across vertebrates, invertebrates, and was traced to unicellular organisms, thus enabling following evolutionary additions and losses of genes or domains. The N-terminal and C-terminal DCX domains have undergone sub-specialization and divergence. Developmental in situ hybridization data for nine genes was generated. In addition, a novel co-expression analysis for most human and mouse DCX superfamily-genes was performed using high-throughput expression data extracted from Unigene. We performed an in-depth study of a complete gene superfamily using several complimentary methods. CONCLUSION: This study reveals the existence and conservation of multiple members of the DCX superfamily in different species. Sequence analysis combined with expression analysis is likely to be a useful tool to predict correlations between human disease and mouse models. The sub-specialization of some members due to restricted expression patterns and sequence divergence may explain the successful addition of genes to this family throughout evolution.

Animals↗
PubMed1977

Duplicate gene expression in diploid and tetraploid loaches (Cypriniformes, Cobitidae).

Botia macracantha and B. modesta have been demonstrated to be tetraploid species on the basis of their karyotypes and on the basis of the expression of a number of isozymes encoded by duplicate loci. A rather low percentage of duplicate loci was detected by electrophoresis, compared to that for other tetraploid Cypriniformes. Several hypotheses have been advanced to account for the low levels of duplicate gene expression observed. Lastly, many of the duplicate loci have diverged to unique patterns of expressions in different tissues or different levels of activity within a single tissue.

Animals↗
PubMed2005

Developmental expression of metalloproteases ADAM 9, 10, and 17 becomes restricted to divergent pancreatic compartments.

The A Disintegrin And Metalloprotease (ADAM) family of metalloproteases affects a variety of proteins with important roles in development and disease, including growth factors and adhesion molecules. We have analyzed the expression patterns of ADAMs 9, 10, and 17 during pancreas ontogeny. All ADAMs investigated were expressed in the pancreatic anlagen but invariably became restricted to divergent pancreatic compartments. ADAM9 and 17 became restricted to the insulin-producing beta-cells and all islet cells, respectively. During embryogenesis, ADAM10 was detected predominantly in acinar cells, but in the adult, it was localized to the cell surface membrane of both endocrine and exocrine cells. In addition to ADAM9, a potential prognostic factor for ductal cancers, we describe the expression of ADAM10 and ADAM17 in the pancreatic ductal epithelium. Altogether, the dynamic expression profile of the ADAM proteases described here may reflect a functional divergence of these as mediators of pancreas biology.

Animals↗
PubMed1999

Quantitative analysis of NF1 and OMGP gene transcripts in sporadic gliomas, sporadic meningiomas and neurofibromatosis type 1-associated plexiform neurofibromas.

The close association of neurofibromatosis type 1 (NF1) with gliomas raises the question of whether the NF1 gene may be involved in the pathogenesis of sporadic astrocytic brain tumors. However, no frequent mutations within NF1 have been described in these tumors. Recent data on a limited series of gliomas indicate that NF1 expression may even be increased, thereby questioning the role of NF1 as a tumor suppressor in astrocytomas. In the present study, we examined the expression of NF1 in a series of 96 tumors including astrocytomas, meningiomas and plexiform neurofibromas. NF1 RNA transcription levels were compared to those of the reference genes B2M, ACTB and GAPD. The expression of OMGP, which is interposed in the NF1 gene, served as an additional control. NF1 expression did not significantly diverge among different malignancy stages of astrocytomas. As expected, the plexiform neurofibromas showed only very low NF1 expression. A striking finding was the highly variable expression of those genes selected to serve as references. While B2M and ACTB exhibited comparable levels of expression within different grades of astrocytomas and meningiomas, GAPD showed an inverse pattern in these tumors. In conclusion, NF1 expression is strongly reduced in NF1-associated plexiform neurofibromas but not in astrocytic tumors. The significant differences between B2M, ACTB and GAPD transcript levels brings into question the common practice of defining gene expression as a ratio between the transcripts of interest and those of these reference genes.

Base Sequence↗
PubMed2006

Localization of TGF-beta signaling intermediates Smad2, 3, 4, and 7 in developing and mature human and mouse kidney.

Smad proteins are signaling intermediates of the TGF-beta superfamily and are involved in a range of biological activities including development and immune responses. We studied the expression of TGF-beta-receptor activated Smads (Smad2 and Smad3), the common partner Smad (Smad4), an inhibitory Smad (Smad7), and the activated (phosphorylated) Smad2 (pSmad2) in developing and adult kidneys of humans and mice. These studies demonstrate associated expression of these Smads in multiple renal cell types in all developmental stages and in mature non-diseased kidneys. Smad expression is in general most widespread at the earliest stages of nephron development and diminishes as components of the nephrons become more differentiated. Paucity of Smad expression in mesangial cells in contrast to widespread expression of these Smads in glomerular visceral epithelial cells in both developing and mature kidneys was remarkable. Divergent and less extensive expression of Smad4, compared with other Smad proteins, was also demonstrated in tubules of human kidneys. Based on the observed expression patterns, these findings demonstrate, for the first time, expression of the TGF-beta-receptor-activated Smad2 and Smad3, the common mediator Smad4, and the inhibitory Smad7 in the developing human fetal kidney, extending observations previously made in rodent systems to humans.

Adult↗
PubMed2000

PDGF B mRNA variants in human tumors with similarity to the v-sis oncogene: expression of cellular PDGF B protein is associated with exon 1 divergence, but not with a 3'UTR splice variant.

While platelet-derived growth factor, PDGF, is not regularly expressed in mesenchymal tissues, PDGF B mRNA is often found in tumors derived from these tissues. PDGF B protein is also present, but the protein levels in individual tumors do not appear to correlate well with those of the mRNA. PDGF B is homologous to the v-sis oncogene of simian sarcoma virus (SSV), and certain deletions confined to 3; and 5; non-coding sequences of PDGF B mRNA are consistently found in tumors induced by SSV and by a PDGF B retrovirus. Part of exon 1, including a non-coding GC-rich regulatory domain and the signal sequence as well as a 149 nucleotide long AU-rich stretch in the 3; non-coding region, are often lost. We hoped that this information could provide a clue to defective regulatory mechanisms present in human tumors and have searched for such mRNA variants in human sarcoma cell lines and soft tissue tumors. We identified a splice variant of PDGF B mRNA that, similar to v-sis, lacks the 149 nucleotide stretch and introduces an anomalous splice point between exons 6 and 7. This weakly abundant mRNA variant was co-expressed with the regular PDGF B mRNA, but its presence failed to show any association with increased levels of immunohistochemically detectable PDGF B protein. Instead, the highest levels of cellular PDGF B protein were found in samples with mRNAs showing exon 1 divergence. The changes in the 5; end of the mRNA were not accompanied by any genomic aberrations.

3' Untranslated Regions↗
PubMed1997

CSF-1 and its receptor in breast carcinomas and neoplasms of the female reproductive tract.

The expression and function of CSF-1 and its receptor were studied in tumors of the human breast, ovary, and endometrium. CSF-1 and its receptor, initially implicated as essential to normal monocyte development and trophoblastic implantation, have been more recently shown to be expressed by carcinomas of the breast and other epithelia of the female reproductive tract where activation of the receptor by ligand produced either by the tumor cells or by stromal elements stimulates tumor cell invasion by a urokinase-dependent mechanism. Breast carcinomas express wild-type CSF-1 receptors (CSF-1R) at levels comparable to those observed in trophoblast and monocytes. Ovarian and endometrial carcinomas express significantly lower levels of wild-type, functional CSF-1Rs, while ovarian carcinomas also express unusual transcripts that diverge from the wild-type CSF-1R transcript in their 5' extracellular domain sequences. Tumor cell expression of CSF-1R is under the control of several steroid hormones (glucocorticoids and progestins) and the binding of several bHLH transcription factors, while tumor cell expression of CSF-1 appears to be regulated by other hormones, some of which are involved in normal lactogenic differentiation. In addition, tumor cells often produce CSF-1 at such high levels that the cytokine spills into the extracellular fluid and circulation. Measurements of circulating levels of CSF-1 have proved useful in patients with ovarian, endometrial, and breast carcinoma both for disease detection and monitoring of response to therapy. CSF-1 and its receptor appear to be an important receptor/ligand pair in the biology of breast cancers and tumors of the female reproductive tract where they may regulate functions similar to those they control during macrophage activation and placental implantation.

Breast Neoplasms↗
PubMed1989

A 165-base pair sequence between the dihydrofolate reductase gene and the divergently transcribed upstream gene is sufficient for bidirectional transcriptional activity.

The dihydrofolate reductase gene encodes a key enzyme of one-carbon metabolism and is constitutively expressed in all cells. Recently, transcripts initiated at 89 base pairs upstream from the transcriptional initiation site of the dihydrofolate reductase gene and transcribed from the opposite strand have been identified and shown to encode for a protein with homology to a bacterial DNA mismatch repair enzyme (Fujii, H., and Shimada, T. (1989) J. Biol. Chem. 264, 10057-10064). Therefore, the two genes are organized in a head-to-head configuration separated by an 89-base pair segment. The promoter activities of this short spacer sequence were studied in a transient assay using the chloramphenicol acetyltransferase and the guanine phosphoribosyltransferase genes as reporters. A 165-base pair fragment from -111 to +54 relative to the dihydrofolate reductase initiation site was shown to be sufficient for transcriptional activity in either direction, suggesting that expression of the two divergent genes is regulated by a bidirectional promoter that may use common regulatory elements.

Animals↗
PubMed2005

Cloning, characterization and tissue expression of rat SULT2B1a and SULT2B1b steroid/sterol sulfotransferase isoforms: divergence of the rat SULT2B1 gene structure from orthologous human and mouse genes.

cDNAs for rat SULT2B1 steroid/sterol sulfotransferase isoforms were cloned, and the encoded proteins overexpressed, purified and characterized. The rat SULT2B1a isoform avidly sulfonates pregnenolone but poorly utilizes cholesterol as a substrate, whereas cholesterol is more efficiently sulfonated than pregnenolone by the SULT2B1b isoform; on the other hand, neither isoform sulfonates dehydroepiandrosterone to any significant degree. Real-time PCR revealed that SULT2B1a was only expressed in brain and testis, whereas SULT2B1b was mainly expressed in skin, intestine and kidney. The SULT2B1 gene is unique among steroid/sterol sulfotransferase genes in that it encodes for two isoforms as a result of an alternative exon I. Interestingly, whereas the orthologous human and mouse SULT2B1 gene structures are identical, the rat SULT2B1 gene structure diverges. Similar to human and mouse SULT2B1 genes the rat SULT2B1 gene consists of an alternative exon I; however, as a result of exonic rearrangement, the genic locations of exons IA and IB are reversed in the rat gene. Where exon IA is located downstream of exon IB in the human and mouse SULT2B1 genes, in the rat SULT2B1 gene exon IA is located upstream of exon IB. Furthermore, unlike the case with human and mouse SULT2B1 genes where differential splicing is necessitated since a portion of exon IA is fused with exon IB to complete the SULT2B1b mRNA, this step is not required with the rat gene.

3' Untranslated Regions↗
PubMed1994

IL-4 and IL-13 have overlapping but distinct effects on HIV production in monocytes.

In HIV-1-infected monocytes and monocytoid cell lines, viral expression can be observed as high-level production, restricted (chronic low-level) expression, and latency (no viral expression). Interleukin-13 (IL-13) and IL-4, which have remarkedly similar deactivating effects on inflammatory monocyte functions, were studied for their regulation of HIV expression in monocytes. Pretreatment of peripheral monocytes for 48-72 h with IL-13 markedly decreased acute HIV infection, whereas IL-4 increased it. Similar effects were seen when the U1 and R-THP-1 monocytoid cell lines with restricted HIV expression were treated with these cytokines. However, when these continuously producing cell lines were chronically treated with cytokines, IL-13 increased HIV production. Neither IL-4 nor IL-13 stimulated HIV expression in latently infected cells. In chronically infected cells, several cytokines reduced viral mRNA. Both IL-4 and IL-13 increased monocyte aggregate formation, but only IL-4 ultimately stimulated cytolysis of HIV-infected monocytes as well as increased apoptosis of U1. In the presence of tumor necrosis factor alpha or IL-6, which upregulate HIV expression, IL-13 could no longer suppress HIV expression. These results indicate that IL-4 and IL-13, although closely related in modulating monocyte function, can have divergent effects on HIV expression in monocytes. Collectively, these data suggest that there exists a complex cytokine tissue environment with positive regulators of HIV expression able to override negative regulators.

Cells, Cultured↗
PubMed1995

CSF-1 and its receptor in ovarian, endometrial and breast cancer.

The aim of this report is to review the role of CSF-1 and its receptor in neoplasms of the breast and female reproductive tract. Expression and function of CSF-1 and its receptor were studied in tumours of the human breast, ovary and endometrium. CSF-1 and its receptor, initially implicated as essential to normal monocyte development and trophoblastic implantation, have been more recently shown to be expressed by carcinomas of the breast, ovary and endometrium where activation of the receptor by ligand produced either by the tumour cells or by stromal elements stimulates tumour cell invasion by a urokinase-dependent mechanism. Breast carcinomas express wild-type CSF-1 receptors at levels comparable to those observed in trophoblast and monocytes. Ovarian and endometrial carcinomas express significantly lower levels of wild-type, functional CSF-1Rs while ovarian carcinomas also express unusual transcripts which diverge from the wild-type CSF-1R transcript in their 5' extracellular and other sequences. Tumour cell expression of CSF-1R is under the control of several steroid hormones (glucocorticoids and progestins) and tumour cell CSF-1 expression appears to be regulated by other hormones, some of which are involved in normal lactogenic differentiation. In addition, tumour cells often produce CSF-1 at such high levels that CSF-1 spills into the extracellular fluid and circulation. Measurements of circulating levels of CSF-1 have proved useful in patients with ovarian, endometrial and breast carcinoma patients both for disease detection and monitoring of response to breast carcinoma patients both for disease detection and monitoring of response to therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
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↗
PubMed1995

Interpreting MHC class I expression and class I/class II reciprocity in the CNS: reconciling divergent findings.

MHC-restricted T cells are thought to contribute to clinical demyelination in MS and other circumstances. The step-by-step mechanisms involved and ways of controlling them are still being defined. Identification of the MHC+ cells in the CNS in situ has been controversial. This chapter reviews MHC expression in neural tissue, including normal, pathological, experimental, and developing tissue in situ and isolated cells in vitro. A basic pattern is defined, in which MHC expression is limited to nonneural cells and strongest class I and II expression are on different cell types. Variations from the basic pattern are reviewed. Ways of reconciling divergent findings are discussed, including the use of "mock tissue" to help choose between technical and biological bases for divergent findings, the potential contribution of internal antigen to the in situ staining patterns, and the possibility that class I upregulation is actively suppressed in situ. Functional implications of the observed patterns of MHC expression and ways of confirming the function of each MHC+ cell type in situ are described. It is suggested that modulating MHC expression in different cell types at different times or in different directions might be desirable.

Animals↗
PubMed1992

Functional relationship between high-affinity E receptor and CD2-11.3 epitope.

The expression of both high-affinity E receptor (EhR) to sheep erythrocytes and CD2-11.3 epitope on activated human T lymphocytes suggests that these two structures may be functionally identical or closely associated. Therefore the aim of the present work was to determine if the CD2-11.3 epitope is involved in the early E rosette formation. The ability of normal and phytohaemagglutin (PHA)-activated human T lymphocytes to express the CD2-11.3 epitope and to form early E rosettes (T cells with EhR) was studied simultaneously. The partial divergence of CD2-11.3 expression on T lymphocytes from the ability of these cells to form early E (Ee) rosettes was found. The results indicated that the expression of CD2-11.3 epitope alone is insufficient to form the Ee rosettes by activated T lymphocytes, yet it may facilitate this phenomenon in the presence of EhR. The above data clearly show that the CD2-11.3 epitope is functionally closely associated although not identical to EhR. Accordingly, it seems that these two structures may co-adhere to the appropriate ligand. Thus it is possible that the CD2-11.3 epitope, as well as its established role in activation signalling, may also act as a co-adhesion molecule.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1991

Divergent genes for translation initiation factor eIF-4A are coordinately expressed in tobacco.

Three cDNA clones coding for eukaryotic translation initiation factor 4A, eIF-4A, were isolated from a Nicotiana plumbaginifolia root cDNA library by heterologous screening. The clones comprise two distinct gene classes as two clones are highly similar while the third is divergent. The genes belong to a highly conserved gene family, the DEAD box supergene family, although the divergent clone contains a DESD box rather than the characteristic DEAD box. The two clones are representatives of separate small multigene families in both N. plumbaginifolia and N. tabacum. Representatives of each family are coordinately expressed in all plant organs examined. The 47 kD polypeptide product of one clone, overexpressed in E. coli, crossreacts immunologically with a rabbit reticulocyte eIF-4A polyclonal antibody. Taken together the data suggest that the two Nicotiana eIF-4A genes encode translation initiation factors. The sequence divergence and the coordinate expression of the two Nicotiana eIF-4A families provide an excellent system to determine if functionally distinct eIF-4A polypeptides are required for translation initiation in plants.

Amino Acid Sequence↗
PubMed2006

Two highly divergent alcohol dehydrogenases of melon exhibit fruit ripening-specific expression and distinct biochemical characteristics.

Alcohol dehydrogenases (ADH) participate in the biosynthetic pathway of aroma volatiles in fruit by interconverting aldehydes to alcohols and providing substrates for the formation of esters. Two highly divergent ADH genes (15% identity at the amino acid level) of Cantaloupe Charentais melon (Cucumis melo var. Cantalupensis) have been isolated. Cm-ADH1 belongs to the medium-chain zinc-binding type of ADHs and is highly similar to all ADH genes expressed in fruit isolated so far. Cm-ADH2 belongs to the short-chain type of ADHs. The two encoded proteins are enzymatically active upon expression in yeast. Cm-ADH1 has strong preference for NAPDH as a co-factor, whereas Cm-ADH2 preferentially uses NADH. Both Cm-ADH proteins are much more active as reductases with K (m)s 10-20 times lower for the conversion of aldehydes to alcohols than for the dehydrogenation of alcohols to aldehydes. They both show strong preference for aliphatic aldehydes but Cm-ADH1 is capable of reducing branched aldehydes such as 3-methylbutyraldehyde, whereas Cm-ADH2 cannot. Both Cm-ADH genes are expressed specifically in fruit and up-regulated during ripening. Gene expression as well as total ADH activity are strongly inhibited in antisense ACC oxidase melons and in melon fruit treated with the ethylene antagonist 1-methylcyclopropene (1-MCP), indicating a positive regulation by ethylene. These data suggest that each of the Cm-ADH protein plays a specific role in the regulation of aroma biosynthesis in melon fruit.

Alcohol Dehydrogenase↗