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Results for “tissue specificity”

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At least 145 records · Page 8Linked to original sources

PubMed2004

Tissue-specific spatial organization of genomes.

BACKGROUND: Genomes are organized in vivo in the form of chromosomes. Each chromosome occupies a distinct nuclear subvolume in the form of a chromosome territory. The spatial positioning of chromosomes within the interphase nucleus is often nonrandom. It is unclear whether the nonrandom spatial arrangement of chromosomes is conserved among tissues or whether spatial genome organization is tissue-specific. RESULTS: Using two-dimensional and three-dimensional fluorescence in situ hybridization we have carried out a systematic analysis of the spatial positioning of a subset of mouse chromosomes in several tissues. We show that chromosomes exhibit tissue-specific organization. Chromosomes are distributed tissue-specifically with respect to their position relative to the center of the nucleus and also relative to each other. Subsets of chromosomes form distinct types of spatial clusters in different tissues and the relative distance between chromosome pairs varies among tissues. Consistent with the notion that nonrandom spatial proximity is functionally relevant in determining the outcome of chromosome translocation events, we find a correlation between tissue-specific spatial proximity and tissue-specific translocation prevalence. CONCLUSIONS: Our results demonstrate that the spatial organization of genomes is tissue-specific and point to a role for tissue-specific spatial genome organization in the formation of recurrent chromosome arrangements among tissues.

Animals↗

PubMed1994

Tyrosine kinase activity may be necessary but is not sufficient for c-erbB1-mediated tissue-specific tumorigenicity.

Expression of mutant avian c-erbB1 genes results in tissue-specific transformation in chickens. Site-directed mutagenesis was used to generate kinase-defective mutants of several tissue-specific v-erbB transforming mutants by replacement of the ATP-binding lysine residue in the kinase domain with an arginine residue. These kinase-defective v-erbB mutants were analyzed for their in vitro and in vivo transforming potentials. Specifically, kinase-defective mutants of erythroleukemogenic, hemangioma-inducing, and sarcomagenic v-erbB genes were assessed for their oncogenic potential. In vitro transformation potential was assessed by soft-agar colony formation in primary cultures of chick embryo fibroblasts (CEF). In vivo transformation potential was determined by infection of 1-day-old line 0 chicks with concentrated recombinant retrovirus and then monitoring of birds for tumor formation. These transformation assays demonstrate that kinase activity is absolutely essential for transformation by tissue-specific transforming mutants of the avian c-erbB1 gene. Since all of the tissue-specific v-erbB mutants characterized to date exhibit tyrosine kinase activity in vitro but do not transform all tissues in which they are expressed, we conclude that v-erbB-associated tyrosine kinase activity may be necessary but is not sufficient to induce tumor formation.

Alpharetrovirus↗

PubMed1988

Na+,K+-ATPase: tissue-specific expression of genes coding for alpha-subunit in diverse human tissues.

The expression of genes coding for alpha and alpha III isoforms of Na+,K+-ATPase alpha-subunit has been studied in human kidney, brain, thyroid and liver cells. The expression was shown to be subjected to a tissue-specific control and also depended on the developmental stage. The tissue-specific expression of genes coding for different isoforms of the catalytic subunit of Na+,K+-ATPase perhaps may be attributed to various functions of proteins belonging to this family.

Adult↗

PubMed2001

DNA sequence comparison of human and mouse retinitis pigmentosa GTPase regulator (RPGR) identifies tissue-specific exons and putative regulatory elements.

Retinitis pigmentosa 3 (RP3) is a progressive retinal degeneration due to mutations in the X-linked RPGR gene. Transcription studies in human and mouse tissues have revealed ubiquitously expressed transcripts and also an exceptional high number of tissue-specific alternative splice variants. However, regulation of tissue-specific expression and splicing is unclear, but this is of particular interest as mutations in this ubiquitously expressed gene lead to severe retinal degeneration, while other tissues are unaffected. To elucidate the conservation pattern of RPGR and to identify additional tissue-specific exons and putative regulatory elements we performed comparative genomic sequencing of the human and mouse RPGR gene. Each of the genes spans a region of nearly 59 kb, and all previously identified exons are conserved between the two species. DNA sequence comparison identified 28 conserved sequence elements (CSEs) in introns, upstream of exon 1, within the promotor region, and downstream of the most 3' exon. Some of the intronic CSEs flank tissue-specific exons and therefore may represent important regulatory elements for alternative splicing. Comparative northern blot hybridization of ubiquitous and tissue-specific RPGR probes identified high molecular weight transcripts with similar expression patterns in both human and mouse. These transcripts range from 6 to 15 kb in size and suggest the presence of additional transcribed sequences within RPGR. Our cross-species sequence comparison enables us to define candidate regions that may explain these large transcripts and will therefore contribute to the understanding of RPGR expression and splicing.

Alternative Splicing↗

PubMed1981

[Tissue-specific regulation of rat liver mitochondrial oxidative phosphorylation by a soluble phase of cells from that organ].

Tissue specificity of mitochondrial respiration stimulation under the effect of a soluble phase of liver cells (SPC) is preserved by addition to dinitrophenol but is reserved in the presence of oligomycin. Addition of rotenon in the presence of SPC entails a tissue-specific increase in respiration that is proportional to the respective increase in respiration of intact mitochondria in the presence of the inhibitor mentioned. SPC tissue-specifically inhibits ATPase activity of liver mitochondria. This fraction of SPC is capable of recovering the coupling of oxidative phosphorylation of mitochondria whose respiration is inhibited by adding ADP. A conclusion is made that SPC is capable not only to decrease tissue-specifically the coupling of intact mitochondria but also to raise it in mitochondria with deranged oxidative phosphorylation. This assures intratissue organization of liver metabolism by means of tissue-specific stabilization of liver cell energy metabolism.

2,4-Dinitrophenol↗

PubMed2000

Heart-specific splice-variant of a human mitochondrial ribosomal protein (mRNA processing; tissue specific splicing).

It has been proposed that splice-variants of proteins involved in mitochondrial RNA processing and translation may be involved in the tissue specificity of mitochondrial DNA disease mutations (Fischel-Ghodsian, 1998. Mol. Genet. Metab. 65, 97-104). To identify and characterize the structural components of mitochondrial RNA processing and translation, the Mammalian Mitochondrial Ribosomal Consortium has been formed. The 338 amino acid (aa) residues long MRP-L5 was identified (O'Brien et al., 1999. J. Biol. Chem. 274, 36043-36051), and its transcript was screened for tissue specific splice-variants. Screening of the EST databases revealed a single putative splice-variant, due to the insertion of an exon consisting of 89 nucleotides prior to the last exon. Screening of multiple cDNA libraries revealed this inserted exon to be present only in heart tissue, in addition to the predominant MRP-L5 transcript. Sequencing of this region confirmed the EST sequence, and showed in the splice-variant a termination triplet at the beginning of the last exon. Thus the inserted exon replaces the coding sequence of the regular last exon, and creates a new 353 aa long protein (MRP-L5V1). Sequence analysis and 3D modeling reveal similarity between MRP-L5 and threonyl-t-RNA synthetases, and a likely RNA binding site within MRP-L5, with the C-terminus in proximity to the RNA binding site. Sequence analysis of MRP-L5V1 also suggests a likely transmembrane domain at the C-terminus. Thus it is possible that the MRP-L5V1 C-terminus could interfere with RNA binding and may have gained a transmembrane domain. Further studies will be required to elucidate the functional significance of MRP-L5V1.

Amino Acid Sequence↗

PubMed2005

Tissue-specific expression of Fgfr2b and Fgfr2c isoforms, Fgf10 and Fgf9 in the developing chick mandible.

Experimental evidence has demonstrated the importance of FGF signalling in morphogenesis of the mandibular processes. FGFs transmit their signals through four tyrosine kinase transmembrane receptors (FGFRs). Alternative splicing in FGFRs including FGFR2 generates different isoforms that exhibit different ligand-specificities, exclusive tissue distributions and specific biological functions. Despite extensive information regarding the isoform-specific patterns of expression Fgfr2c and Fgfr2b during morphogenesis of many organs, a comparative analysis of these specific isoforms in the chick mandible has not been reported. To better understand the function of FGFR2 in mandibular morphogenesis, we have analysed the expression Fgfr2b, Fgfr2c and their putative ligands Fgf10 and Fgf9, in the developing chick mandibular processes by in situ hybridisation and RT-PCR. Our observations show that Fgfr2b was primarily expressed in the mandibular epithelium while Fgfr2c was expressed in the mandibular mesenchyme including Meckel's cartilage. Fgf9 and Fgf10 were expressed in a variety of craniofacial regions including the mandibular epithelium and mesenchyme respectively. The temporal and spatial distributions of Fgfr2b, Fgfr2c, Fgf10 and Fgf9 in the developing mandible reported in this study make them attractive candidates for involvement in epithelial-mesenchymal signalling interactions that are known to be necessary for proper mandibular outgrowth and morphogenesis.

Animals↗

PubMed2001

Establishment of a novel species- and tissue-specific metastasis model of human prostate cancer in humanized non-obese diabetic/severe combined immunodeficient mice engrafted with human adult lung and bone.

Bone is the most common site of metastasis in prostate cancer (PC), and to generate an animal model to investigate the basis of the unique organ tropism of PC cells for bone, we engrafted humanized non-obese diabetic/severe combined immunodeficient (NOD/SCID-hu) mice with human adult bone (HAB) and lung (HAL). Human PC cell lines LNCaP (1 x 10(7)) and PC-3 (5 x 10(6)) were injected into male NOD/SCID-hu mice via the lateral tail vein at 3-4 weeks after implantation. At 8 weeks after the injection, LNCaP and PC-3 cells had metastasized specifically to HAB in 35 and 65%, respectively, of the mice. The tumors formed by LNCaP appeared to be the osteoblastic type, whereas the PC-3 tumors consisted of osteolytic lesions without any surrounding osteogenic response. A feature of experimental metastasis of PC in NOD/SCID-hu mice was its specificity for HAB tissue. Human PC cells had no or very low metastatic potential in regard to implanted HAL, mouse bone, or native mouse bone. These findings indicate that metastasis of PC cells to HAB is both species and tissue specific. The availability of this small animal model could provide a useful tool for identifying and analyzing important features of the human PC metastatic process that cannot be addressed in conventional metastasis models.

Aged↗

PubMed2004

Systems for regulated or tissue-specific gene expression.

The achievement of efficient regulation and/or tissue-specific gene expression is one of the major goals for gene therapists. A number of inducible systems and tissue-specific promoters are currently available. Studies in vitro and in vivo have shown promising results in controlling gene expression. However, the achievement of efficient gene regulation in patients is still an open question. This review describes the main inducible systems and tissue-specific promoters in view of their potential therapeutic applications.

Animals↗

PubMed2005

Variation in tissue-specific gene expression among natural populations.

BACKGROUND: Variation in gene expression is extensive among tissues, individuals, strains, populations and species. The interactions among these sources of variation are relevant for physiological studies such as disease or toxic stress; for example, it is common for pathologies such as cancer, heart failure and metabolic disease to be associated with changes in tissue-specific gene expression or changes in metabolic gene expression. But how conserved these differences are among outbred individuals and among populations has not been well documented. To address this we examined the expression of a selected suite of 192 metabolic genes in brain, heart and liver in three populations of the teleost fish Fundulus heteroclitus using a highly replicated experimental design. RESULTS: Half of the genes (48%) were differentially expressed among individuals within a population-tissue group and 76% were differentially expressed among tissues. Differences among tissues reflected well established tissue-specific metabolic requirements, suggesting that these measures of gene expression accurately reflect changes in proteins and their phenotypic effects. Remarkably, only a small subset (31%) of tissue-specific differences was consistent in all three populations. CONCLUSIONS: These data indicate that many tissue-specific differences in gene expression are unique to one population and thus are unlikely to contribute to fundamental differences between tissue types. We suggest that those subsets of treatment-specific gene expression patterns that are conserved between taxa are most likely to be functionally related to the physiological state in question.

Animals↗

PubMed1995

Integrating sex- and tissue-specific regulation within a single Drosophila enhancer.

We have investigated the integration of sex- and tissue-specific transcriptional regulation in Drosophila. A single copy of the o-r enhancer from yolk protein genes directs female- and fat body-specific transcription. It consists of four protein-binding sites: dsxA, which binds male (DSXM) and female (DSXF) proteins encoded by the doublesex gene; aef1, which binds the AEF1 repressor; bzip1, which binds the DmC/EBP activator encoded by the slbo gene; and ref1, which binds an unknown activator. Multimeric and mutated binding sites were used in protein binding, germ-line transformation, and genetic experiments to examine the independent and combinatorial activities of the proteins and DNA sites. DSXF activates from dsxA by sterically excluding AEF1 repressor from the aef1 site and synergistically activating transcription together with a protein at bzip1. Sex specificity in fat bodies arises from the opposite effect of DSXM, which represses activity of the protein at bzip1. Tissue specificity is regulated by all four DNA sites. Separately, bzip1 and ref1 activate transcription in ovarian somatic cells and all nongonadal tissues, respectively, whereas together they activate only in fat bodies. The aef1 site represses ectopic transcription in ovaries and dsxA antirepresses this activity in fat bodies. Thus, in the organism, ref1 and bzip1 act combinatorially to direct the fundamental tissue specificity, aef1 and dsxA modulate this tissue specificity, and dsxA adds sex specificity.

Animals↗

PubMed1995

Tissue-specific regulation of the insulin gene by a novel basic helix-loop-helix transcription factor.

The insulin gene is one of the best paradigms of tissue-specific gene expression. It is developmentally regulated and is expressed exclusively in the pancreatic beta-cell. This restricted expression is directed by a tissue-specific enhancer, within the promoter, which contains an E-box sequence. The insulin E-box binds an islet-specific protein complex, termed 3a1. E-boxes bind proteins belonging to the basic helix-loop-helix (bHLH) family of transcription factors. The bHLH proteins function as potent transcriptional activators of tissue-specific genes by forming heterodimers between ubiquitous and cell-restricted family members. In addition, the cell-restricted bHLH members play an important role in specifying cell fate. To isolate the tissue-specific bHLH factor controlling insulin gene expression and study its role in islet cell differentiation, a modified yeast two-hybrid system was utilized to clone a novel bHLH factor, BETA2 (beta-cell E-box trans-activator 2), from a hamster insulin tumor (HIT) cell cDNA library. Northern analysis demonstrates that high-level expression of the BETA2 gene is restricted to pancreatic alpha- and beta-cell lines. As expected of tissue-specific bHLH members, BETA2 binds to the insulin E-box sequence with high affinity as a heterodimer with the ubiquitous bHLH factor E47. More importantly, antibody supershift experiments clearly show that BETA2 is a component of the native insulin E-box-binding complex. Transient transfection assays demonstrate that the BETA2/E47 heterodimer synergistically interacts with a neighboring beta-cell-specific complex to activate an insulin enhancer. In contrast, other bHLH factors such as MyoD and E47, which can bind to the insulin E-box with high affinity, fail to do so. Thus, a unique, cooperative interaction is the basis by which the insulin E-box enhancer discriminates between various bHLH factors to achieve tissue-specific activation of the insulin gene.

Amino Acid Sequence↗

PubMed2003

Human Oct-1L isoform has tissue-specific expression pattern similar to Oct-2.

POU homeodomain proteins are important regulators of ubiquitous as well as tissue-specific transcription. Ubiquitously expressed Oct-1 and tissue-specific Oct-2 proteins are members of the POU family and contain very similar DNA-binding POU domains. While Oct-1 is ubiquitous, Oct-2 is predominantly expressed in B cells, in activated T cells and in nervous system. Oct-1 is involved in regulation of some houskeeping genes-histone H2B, snRNAs as well as in tissue-specific regulation of immunoglobuline gene transcription and of some other genes. Here we report that novel alternatively spliced product of the human Oct-1 gene encode Oct-1L isoform with tissue-specific expression pattern, similar to Oct-2. Oct-1L differ from ubiquitously expressed Oct-1A in 5'-terminal exon (exon 1L). Analysis of nucleotide sequences from Human Genome Data Bank has located exon 1L about 108 kbp downstream ubiquitously expressed exon 1U. Amino terminus of Oct-1L show extensive similarity to amino terminus of Oct-2. We suppose, that Oct-1L may has a specific role in gene expression in lymphoid tissues and brain.

Alternative Splicing↗

PubMed2026

Changes in the transcriptome and synthetic lethal dependencies following KRAS mutant expression reveal profound tissue specificity.

Oncogenic KRAS mutations exhibit a striking tissue-restricted tropism, occurring with high frequency in pancreatic, colorectal, and lung adenocarcinomas while remaining rare in other lineages. The molecular basis for why these specific tissues are uniquely permissive to KRAS transformation, and how this context shapes therapeutic vulnerabilities, remains poorly defined. Here, we utilized CRISPR-mediated genome engineering to generate endogenous, conditional KRAS-mutant isogenic cell line models across three primary permissive lineages (lung, colon, and pancreas) and the nonpermissive breast lineage. Integrated genome-wide CRISPR fitness screens and comparative transcriptome analyses revealed that KRAS-driven synthetic lethal (SL) dependencies are profoundly shaped by their tissue of origin. Strikingly, we observed minimal overlap in SL hits across lineages, with only three genes shared among the permissive lines, suggesting that the KRAS oncogene operates through divergent, context-specific genetic networks. Mechanistically, we show that KRAS activation induces a universal MYC-driven metabolic signature, but the specific machinery required to sustain this state is lineage-restricted. We identified a dependency on the diphthamide synthesis pathway to maintain translational fidelity amid a KRAS-induced hypertranslational state. These findings demonstrate that even when driven by the same oncogene, tumors exhibit distinct regulatory landscapes and unique genetic vulnerabilities. Our results provide a framework for developing lineage-aware therapeutic strategies, moving beyond universal KRAS inhibition toward targeted interventions tailored to a tumor's specific tissue context.

Proto-Oncogene Proteins p21(ras)↗

PubMed2001

Expression of the rabbit cytochrome P450 aromatase encoding gene uses alternative tissue-specific promoters.

The aim of the present study was to analyse the tissue-specific expression of various promoter-derived transcripts from the gene encoding rabbit aromatase cytochrome P450. A new promoter, named I.r, was identified, and promoters II and I.r were sequenced. Promoter I.r-derived transcripts were found in preovulatory granulosa cells, corpus luteum, placenta and adipose tissue. An alternative splice variant of this transcript was found with tissue-specific preference. Tissue-specific expression of promoter-derived variants was studied in the ovary before and after ovulation. While the level of promoter II-derived transcript decreased dramatically after ovulation, that of promoter I.r-derived transcript remained unchanged, indicating that promoter II and promoter I.r were not controlled by a single regulation system. The existence of this dual system of regulation suggests that the rabbit ovary could be a useful model to study the promoter-specific regulation of aromatase.

Alternative Splicing↗

PubMedDate not supplied

Development of a new plasmid vector with PSA-promoter and enhancer expressing tissue-specificity in prostate carcinoma cell lines.

Differential expression of the desired gene product in the target tissue is central to the concept of gene therapy. One approach is to use a tissue-specific promoter to drive therapeutic genes, such as the p53 tumor suppressor gene. To determine the feasibility of tissue-specific gene therapy for prostate cancer using prostate specific antigen (PSA) promoter and/or enhancer, in this study, we developed a tissue specific expression vector using a PSA promoter and enhancer. Our results showed that the cloned PSA promoter actively drives gene expression in the PSA-producing prostate cancer cell line (LNCaP). However, barely any promoter activity was detected in the non-PSA producing prostate cancer cell lines (DU145, PC-3) or the non-prostate cell lines (HEK-293, SAOS-2). The wild-type p53 gene driven by this PSA-promoter efficiently suppressed the growth of LNCaP. Moreover, p53 driven by the PSA enhancer-promoter cassette more efficiently suppressed the growth of the PSA-producing prostate cancer cell line (LNCaP) in vitro. This suggest that we were able to manage the tissue specificity by PSA enhancer and promoter. Additionally, the juxtaposed enhancer-promoter cassette showed great enhancement of p53 expression and apoptosis in vitro. Taken together, these results show that PSA enhancer-promoter may be a potential tool for gene therapy for prostate cancer.

Adenocarcinoma↗

PubMed1989

Clonal growth of tumors on tissue-specific biomatrices and correlation with organ site specificity of metastases.

We have found that neoplastic transformation alters the ability of cells to grow on substrata of tissue extracts, "biomatrices", enriched in extracellular matrix. Tumor cells were able to survive and grow at lower densities and on more types of biomatrices than normal cells. When plated at high densities (greater than 10(5) cells/60 mm dish), tumor cells attached with equal efficiency and grew at similar rates and to equivalent saturation densities on biomatrices derived from all tissues. However, at low (10(2)-10(4)/60-mm dish) seeding densities, the tumor cells grew only on certain types of biomatrix. For the various hepatoma and mammary carcinoma cell lines tested, the tissue specificity in clonal growth on biomatrices correlated with their organ site specificity for metastasis in vivo in immunosuppressed, athymic nude mice. Analysis of the effects of purified matrix components (adhesion proteins, collagens, glycosaminoglycans) indicated that only the glycosaminoglycans influenced density-dependent survival and growth of tumor cells with effects that differed with respect to the cell's metastatic potential. The results indicate that the ability of tumor cells to colonize specific tissues represents, in part, regulation of low density survival and growth by extracellular matrix and are suggestive that one of the matrix components responsible may be proteoglycans or their glycosaminoglycan chains.

Animals↗

PubMed1988

[Tissue specificity of chordin].

Chordin is a tissue-specific protein antigen of notochord. Earlier this protein was discovered in the notochords of sturgeon (Acipenseridae) species; the notochord-specific antigenic determinants were detected in the notochord residues of teleost fish species and in notochord derivatives (nuclei pulposi) of mammals. Using the RIA technique, extracts from 35 samples of normal, fetal and tumour tissues of man were screened for chordin. Among other tissue samples tested, extracts from fetal brain and rectal adenocarcinoma exhibited marked cross-reactivity towards antibodies against chordin. Cross-reactivity towards chordin was observed in rabbit brain extract. This extract contained an antigen which was immunologically related (but not fully identical) to chordin. In total, in this and previous studies, 58 samples of fish and mammalian tissues were analyzed for chordin. However, antigenic determinants of chordin were identified only in extracts prepared from the notochords and nuclei pulposi as well as from brain and rectal adenocarcinoma. These findings suggest that chordin is an antigen with a restricted tissue specificity.

Animals↗