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Biomedical subjects

R Axel

Publications and source records attributed to R Axel.

At least 73 records · Page 4Linked to original sources
PubMed1987

Structure and expression of the human and mouse T4 genes.

The T4 molecule may serve as a T-cell receptor recognizing molecules on the surface of specific target cells and also serves as the receptor for the human immunodeficiency virus. To define the mechanisms of interaction of T4 with the surface of antigen-presenting cells as well as with human immunodeficiency virus, we have further analyzed the sequence, structure, and expression of the human and mouse T4 genes. T4 consists of an extracellular segment comprised of a leader sequence followed by four tandem variable-joining (VJ)-like domains, a transmembrane domain, and a cytoplasmic segment. The structural domains of the T4 protein deduced from amino acid sequence are precisely reflected in the intron-exon organization of the gene. Analysis of the expression of the T4 gene indicates that T4 RNA is expressed not only in T lymphocytes, but in B cells, macrophages, and granulocytes. T4 is also expressed in a developmentally regulated manner in specific regions of the brain. It is, therefore, possible that T4 plays a more general role in mediating cell recognition events that are not restricted to the cellular immune response.

Amino Acid Sequence↗
PubMed1987

Characterization of two members of the rho gene family from the yeast Saccharomyces cerevisiae.

The rho genes comprise an evolutionarily conserved family with significant homology to the ras oncogene family. Two members of the rho family were isolated from the yeast Saccharomyces cerevisiae and characterized by DNA sequence analysis. The yeast genes RHO1 and RHO2 are 70% and 57% identical, respectively, to the rho gene of the marine snail Aplysia, and they are 53% identical to each other. Inactivation of these genes showed that RHO1 is required for cell viability, while RHO2 is not an essential gene. A mutant allele of RHO1 (RHO1-His68) was constructed with a mutation analogous to one that activates the transforming potential of the human HRAS gene. Diploid strains containing RHO1-His68 in either low or high copy number are unable to sporulate, and the mutant allele is dominant over wild-type RHO1. The requirement for RHO1 cannot be circumvented by introduction of high copy number plasmids containing either the gene encoding the catalytic subunit of cAMP-dependent protein kinase or the mutant allele RAS2-Val19. Despite the conservation between the rho and ras gene families, the finding that RHO1 functions independently of the adenylate cyclase cAMP-dependent protein kinase cascade suggests that rho and ras are involved in distinct biochemical pathways.

Alleles↗
PubMed1987

Glucocorticoids enhance stability of human growth hormone mRNA.

We have studied the control of expression of the human growth hormone (hGH) gene introduced into the chromosomes of mouse fibroblasts. Cell lines transformed with the hGH gene expressed low levels of intact hGH mRNA and secreted hGH protein into the medium. Although the level of expression of hGH mRNA was low, the gene remained responsive to induction by glucocorticoid hormones. To localize the sequences responsible for induction and to determine the mechanism by which these cis-acting sequences enhance gene expression, we have constructed a series of fusion genes between the hGH gene and the herpes simplex virus (HSV) thymidine kinase (tk) gene. We have demonstrated that a fusion gene in which hGH cDNA is flanked at its 5' terminus by an HSV tk promoter and is flanked at its 3' terminus by 3' HSV tk DNA remains inducible by glucocorticoids. Our studies indicate that the hGH exons contain sequences which are responsible for glucocorticoid hormone induction. Pulse-chase experiments, in vitro nuclear transcription, and approach to steady-state measurements indicate that the mechanisms responsible for induction of the hGH cDNA fusion gene operate posttranscriptionally to enhance the stability of hGH mRNA. Moreover, this increased stability was associated with an increase in the length of the 3' poly(A) tail on hGH mRNA.

Animals↗
PubMed1986

A bipotential neuroendocrine precursor whose choice of cell fate is determined by NGF and glucocorticoids.

Adrenal medullary endocrine (chromaffin) cells and sympathetic neurons both derive from the neural crest. We have found that the embryonic adrenal medulla and sympathetic ganglia are both initially populated by precursors expressing neural-specific genes. By birth, however, the medulla consists largely of chromaffin cells. In primary culture, the medullary precursors have three developmental fates: in NGF they continue to mature into neurons and survive, whereas in glucocorticoid they either extinguish their neuronal properties and exhibit an endocrine phenotype, or else continue to develop into neurons but then die. These data suggest that, in vivo, the adrenal medulla develops through both the glucocorticoid-induced differentiation of bipotential progenitors and the degeneration of committed neuronal precursors, which have migrated into the gland.

Adrenal Medulla↗
PubMed1986

The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain.

The isolation of clones encoding the human surface protein T4, and the expression of the T4 gene in new cellular environments, have enabled us to examine the role of this protein in the pathogenesis of AIDS. Our studies support a mechanism of AIDS virus infection that initially involves the specific interaction of the AIDS virus with T4 molecules on the cell surface. This association can be demonstrated on T4+ transformed T and B lymphocytes as well as epithelial cells. Furthermore, the presence of T4 on the surface of all human cells examined is sufficient to render these cells susceptible to AIDS virus infection. Our data suggest that the T4-AIDS virus complex is then internalized by receptor-mediated endocytosis. Finally, we find that the T4 gene is expressed in the brain as well as in lymphoid cells, providing an explanation for the dual neurotropic and lymphotropic character of the AIDS virus. In this manner, a T lymphocyte surface protein important in mediating effector cell-target cell interactions has been exploited by a human retrovirus to specifically target the AIDS virus to populations of T4+ cells.

Ammonium Chloride↗
PubMed1986

Nucleosomes are phased along the mouse beta-major globin gene in erythroid and nonerythroid cells.

We have used the chemical cleavage reagent methidiumpropyl-EDTA-Fe(II) to determine the location of the nucleosomes along the mouse beta-major globin gene in erythroid and nonerythroid cells. In mouse L cells, in which the globin gene is inactive, the nucleosomes are precisely positioned with respect to the underlying DNA sequence from positions -3000 to +1500 relative to the cap site. In uninduced and induced murine erythroleukemia cells, the same phasing persists but is interrupted from positions -200 to +500. This gap in the phased distribution of nucleosomes appears to be protected from MPE-Fe(II) digestion, and is bounded on both sides by hypersensitive sites. These results define at least two structural states for the globin gene: an inactive state in which the gene is covered with a continuous array of phased nucleosomes and an active state in which this array is disrupted over the 5' half of the structural gene.

Animals↗
PubMed1986

Molecular cloning and nucleotide sequence of the streptavidin gene.

Using synthetic oligonucleotides as probes we have cloned the streptavidin gene from a genomic library of Streptomyces avidinii. Nucleotide sequence analysis indicated that a 2 Kb DNA-fragment contained the entire coding region, a signal peptide region and the 3' and 5' flanking regions of the gene. The deduced amino acid sequence shows several interrupted blocks of homology with the amino acid sequence of chicken egg-white avidin. Analysis of the secondary structure suggests a high content of beta-structure in both proteins and considerable overall structural similarity between them.

Amino Acid Sequence↗
PubMed1986

The gene encoding the T-cell surface protein T4 is located on human chromosome 12.

The surface glycoproteins T4 and T8 define functionally distinct populations of T lymphocytes. We have obtained cDNA and genomic clones encoding the T4 molecule and used these as probes to determine the chromosomal location of this gene. Genomic blotting experiments, along with in situ hybridization analyses, indicate that the T4 gene resides on the short arm of human chromosome 12, at region p12-pter. Thus, the T4 gene is not linked to any known member of the immunoglobulin gene family, including its counterpart gene, T8, which resides on human chromosome 2 immediately distal to the immunoglobulin kappa locus.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1986

The T4 glycoprotein is a cell-surface receptor for the AIDS virus.

Taken together, our studies suggest a mechanism of AIDS virus infection that initially involves the specific association of the AIDS virus with T4 molecules on the cell surface. This association does not require additional T-cell-specific molecules and can be demonstrated on both B lymphocytes and epithelial cell lines. The T4-AIDS virus complex is likely to be internalized in endosomes via receptor-mediated endocytosis. The virus can then fuse with the vacuolar membrane, releasing the viral nucleocapsid into the cytoplasm to undergo uncoating. Viral replication does not appear to require the environment of a T lymphocyte because active infection is also observed in human T4+ B lymphocytes and epithelial cell lines. Moreover, the T4 gene is expressed in the brain as well as in lymphocytes, providing an explanation for the dual neurotropic and lymphotropic character of the virus. In this manner, a T-lymphocyte surface protein thought to be important in mediating effector cell-target cell interactions has been exploited by a human lymphotropic virus to target the AIDS virus specifically to populations of T4+ cells.

Acquired Immunodeficiency Syndrome↗
PubMed1985

A novel ras-related gene family.

We have identified a new family of ras genes, the rho genes, which share several properties with the more classical ras gene family consisting of N-, K-, and H-ras. The rho genes, first isolated from a cDNA library from the abdominal ganglia of Aplysia, encode proteins that share 35% amino acid homology with H-ras. Evolutionarily conserved counterparts of rho have been detected in yeast, in Drosophila, in rat, and in man. Sequence analysis reveals over 85% homology between the human and Aplysia proteins. The ras and rho gene products share several common properties; both are 21,000 daltons, both reveal C-terminal sequences required for membrane attachment, and both show blocks of strong internal homology, suggesting that the two proteins may share common functions but may use these functions in different ways.

Amino Acid Sequence↗
PubMed1985

Molecular probes for the development and plasticity of neural crest derivatives.

We have isolated cDNA clones for several mRNAs expressed in sympathetic neurons but not in adrenal chromaffin cells, two neural crest derivatives thought to share a common precursor. The tissue specificity, developmental expression, and hormonal regulation of these genes have been characterized using Northern blot and in situ hybridization analysis. We find that these mRNAs are independently regulated in development rather than synchronously induced. Our evidence also implicates Nerve Growth Factor (NGF) in the induction of one of these genes in postmigratory crest cells. Two of these genes become induced in mature chromaffin cells, which express a neuronal morphology in response to NGF. These results support the idea that the phenotypic plasticity of neural crest derivatives reflects a common precursor, the multipotentiality of which is sustained through terminal differentiation.

Adrenal Medulla↗
PubMed1985

The isolation and sequence of the gene encoding T8: a molecule defining functional classes of T lymphocytes.

The T cell surface glycoproteins T4 and T8 are thought to mediate efficient cell-cell interactions in the immune system and in this way may be responsible for the appropriate targeting of subpopulations of T cells. We have used gene transfer combined with subtractive hybridization to isolate both cDNA and functional genomic clones encoding the T8 protein. The sequence of the cDNA reveals that T8 is a transmembrane protein with an N-terminal domain which shares significant homology to immunoglobulin variable region light chains. This immunoglobulin-like structure is likely to be important in the function of T8 during differentiation and in the course of the immune response.

Amino Acid Sequence↗
PubMed1985

Isolation and sequence of a cDNA encoding the major structural protein of peripheral myelin.

The myelin sheath is a multilayered membrane, unique to the nervous system, which functions as an insulator to increase greatly the velocity of axonal impulse conduction. We have used the techniques of differential screening and hybrid selection to identify a cDNA clone encoding the Schwann cell glycoprotein P0, the major structural protein of the peripheral myelin sheath. The sequence of this protein, deduced from the nucleotide sequence of the cloned cDNA, indicates that P0 is an integral membrane protein containing a single membrane-spanning region, a large hydrophobic extracellular domain, and a smaller basic intracellular domain. The structure of the protein suggests that each of these domains plays an essential role in generating the highly ordered structure of the myelin sheath. Furthermore, we find that the induction of P0 mRNA coincides with the initiation of myelin formation, and we propose a model in which the glycoprotein serves as a molecular guidepost for this process.

Amino Acid Sequence↗
PubMed1985

The isolation and nucleotide sequence of a cDNA encoding the T cell surface protein T4: a new member of the immunoglobulin gene family.

The surface glycoproteins T4 and T8 define different functional subsets of T lymphocytes and may act as recognition molecules mediating appropriate interactions between the T cell and its target. Previously we employed gene transfer and subtractive hybridization to isolate a T8 cDNA; now we have isolated and sequenced a cDNA clone encoding the T4 molecule. The deduced protein sequence reveals that T4 is an integral membrane protein that shares significant amino acid and structural homologies with members of the immunoglobulin supergene family. The overall structure of T4 consists of an N-terminal variable (V)-like domain, a joining (J)-like region, a third extracellular domain, a membrane-spanning region homologous to class II MHC beta-chains, and a highly charged cytoplasmic domain. Comparison of the protein sequences deduced from the T4 and T8 cDNAs reveals structural similarities consistent with their postulated role as recognition molecules, as well as differences suggesting that the two proteins recognize different structures on the target cell.

Amino Acid Sequence↗
PubMed1984

Human alpha- and beta-globin gene transcription in mouse erythroleukaemia cells.

Human beta-globin genes introduced into mouse erythroleukaemia (MEL) cells by DNA co-transformation are correctly regulated when erythroid cell differentiation is induced by dimethylsulphoxide (DMSO). In contrast, cloned human alpha-globin genes are efficiently transcribed in MEL cells before induction, and no increase in the level alpha-globin mRNA is observed when the cells differentiate. These observations suggest that the mechanisms by which alpha- and beta-globin genes are activated during erythroid cell differentiation are fundamentally different. Analysis of the transcription of hybrid human alpha-beta-globin genes in MEL cells revealed that the sequences responsible for differences in transcription of the intact alpha- and beta-globin genes are located on the 3' side of the mRNA capping site of the two genes, suggesting that cis-acting regulatory sequences are located within the structural genes.

Animals↗
PubMed1984

Differences in human alpha- and beta-globin gene expression in mouse erythroleukemia cells: the role of intragenic sequences.

Human beta-globin genes introduced into mouse erythroleukemia (MEL) cells by DNA cotransformation are correctly regulated when erythroid cell differentiation is induced by dimethylsulfoxide (DMSO). In contrast, cloned human alpha-globin genes are efficiently transcribed in MEL cells prior to induction, and no increase in the level of alpha-globin mRNA is observed when the cells differentiate. These observations suggest that the mechanisms by which alpha- and beta-globin genes are activated during erythroid cell differentiation are fundamentally different. Analysis of the transcription of hybrid human alpha/beta-globin genes in MEL cells revealed that the sequences responsible for differences in transcription of the intact alpha- and beta-globin genes are located on the 3' side of the mRNA capping site of the two genes, suggesting that cis-acting regulatory sequences are located within the structural genes.

Animals↗