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J M Adams

Publications and source records attributed to J M Adams.

At least 19 recordsLinked to original sources
PubMed1992

GATA-1 but not SCL induces megakaryocytic differentiation in an early myeloid line.

GATA-1, a transcription factor of the 'zinc-finger' family, is required for the development of mature erythroid cells and is also highly expressed in the megakaryocytic and mast cell lineages. The helix-loop-helix gene SCL (or TAL) is expressed in the same three hematopoietic lineages as GATA-1. To explore the role of GATA-1 and SCL in hematopoietic differentiation, we introduced a new expression vector bearing each gene into the early myeloid cell line 416B, which could originally differentiate in vivo along the megakaryocytic and granulocytic lineages. Enforced expression of SCL at high levels did not provoke differentiation, but GATA-1 induced the appearance of megakaryocytes as assessed by morphology, the presence of acetylcholinesterase and a polyploid DNA content. Although GATA-1 is thought to stimulate its own transcription in erythrocytes, expression of the endogenous gene was not increased in the megakaryocytic lines; hence GATA-1 may not be autoregulatory in this lineage. Megakaryocytic differentiation was accompanied by a marked decrease in the myeloid surface marker Mac-1. The absence of mast cell or erythroid differentiation suggests that GATA-1 may not be sufficient to provoke maturation along these lineages or that these pathways are impeded in 416B cells. These results demonstrate that a member of the GATA gene family can act as an important regulator of megakaryocytic differentiation.

Acetylcholinesterase↗
PubMed1992

Nucleotide sequence of bup, an upstream gene in the bmi-1 proviral insertion locus.

The ability of Moloney murine leukemia virus to accelerate lymphomagenesis in E mu-myc transgenic mice is frequently associated with proviral integration within a locus denoted bmi-1. This locus contains not only the bmi-1 gene implicated as a collaborator with myc in lymphomagenesis but also just upstream an unknown gene denoted bup. The nucleotide sequence reported here for bup cDNA and flanking genomic sequences reveals that this widely expressed gene comprises at least 7 exons and potentially encodes a polypeptide of 195 amino acid residues. Computer searches with this polypeptide sequence revealed no close homolog in the databases, nor any conserved motifs, and it is unrelated to the product of the mel-13 gene, which lies just upstream from the bmi-1 homolog mel-18.

Amino Acid Sequence↗
PubMed1992

Oncogene co-operation in leukaemogenesis.

The multistep development of haematopoietic malignancies, like other neoplasms, reflects sequential mutations that either activate proto-oncogenes or disrupt tumour suppressor genes. In a few spontaneous leukaemias or lymphomas, more than one mutation has now been identified, and the experimental analysis of oncogene co-operation is advancing rapidly via retroviral gene delivery and characterization of transgenic mice bearing oncogenes. In transgenic models, tumorigenesis can be accelerated by introducing another oncogene or by using a retrovirus as an insertional mutagen to identify cellular genes that collaborate with the transgene. Leukaemogenesis can be promoted by some ten pairs of oncogenes. The myc nuclear oncoprotein, for example, can collaborate with cytoplasmic oncoproteins such as ras, raf, bcl-2, pim-1 and v-abl, as well as with nuclear products such as bmi-1 or the tumour suppressor p53. The genes in such partnerships seem to provide complementary functions. For example, myc seems to prevent cells from becoming quiescent, whereas bcl-2 blocks programmed cell death; and others, for example ras, may diminish growth factor requirements. The products of genes that collaborate may lie on separate signal transduction pathways, leading to distinct nuclear targets. Key targets are postulated to be regulators of the cell cycle, especially the cyclins and associated kinases that govern progression in the G1 phase.

Animals↗
PubMed1992

The hematopoietically expressed vav proto-oncogene shares homology with the dbl GDP-GTP exchange factor, the bcr gene and a yeast gene (CDC24) involved in cytoskeletal organization.

The vav proto-oncogene encodes a protein of unknown function that is rendered oncogenic by loss of a short N-terminal domain. A correction reported here to the vav sequence reveals that a central domain of some 230 amino acids is similar to the products of three genes: the human dbl oncogene, now known to encode a GDP-GTP exchange factor for the Ras-like polypeptide CDC42Hs; the CDC24 gene of Saccharomyces cerevisiae, which participates with CDC42Sc in organization of the cytoskeleton for budding; and the human bcr gene, which recombines with the abl oncogene in certain forms of leukemia. Furthermore, the N-terminal portion of Vav (and of CDC24) is similar to that of certain proteins that associate with filamentous structures. These similarities suggest that Vav, and perhaps also Bcr, may function as a GDP-GTP exchange factor for a Ras-like molecule such as CDC42Hs, and that its action may coordinate cytoplasmic architecture with the cell cycle. Reported evidence that the vav proto-oncogene is widely expressed in hematopoietic cells but not other cell types is extended here by detection of vav mRNA in 49 of 50 murine hematopoietic cell lines representing diverse hematopoietic lineages, and by in situ hybridization in embryos showing expression confined to the only hematopoietic tissue, fetal liver. Thus, like Dbl in other cell types, Vav may function throughout the hematopoietic compartment to govern a Ras-like signal transduction pathway.

Amino Acid Sequence↗
PubMed1992

Retroviral infection accelerates T lymphomagenesis in E mu-N-ras transgenic mice by activating c-myc or N-myc.

Transgenic mice bearing a mutant, activated N-ras oncogene directed to express within hematopoietic cells by an immunoglobulin enhancer (E mu) sporadically develop T-cell lymphomas and non-lymphoid tumors that may be of macrophage origin. To identify genes that can collaborate with N-ras in hematopoietic neoplasia, Moloney murine leukemia virus was used as an insertional mutagen. Infection of newborn E mu-N-ras mice with the virus greatly accelerated tumorigenesis, and nearly all the tumors proved to be T-cell lymphomas. Their variable surface phenotype (CD4+CD8-, CD4+CD8+ and CD4-CD8-) suggested that cells at several stages of T-cell development were susceptible to tumorigenesis. Southern blot analysis revealed that 68% of the tumors bore a proviral insert 5' to the c-myc gene, while 13% had an insert within the 3' untranslated region of the N-myc gene. Insertion was associated with elevated expression of these genes. Hence, activation of a myc gene appears to be the dominant pathway to tumorigenesis by insertional mutagenesis in lymphoid cells expressing a mutant ras gene. However, since many of the tumors were not transplantable, even the partnership of myc and ras may not suffice for full lymphoid malignancy.

Animals↗
PubMed1992

Effect of chloride transport blockade on the MAC of halothane in the rat.

There is a growing evidence that central nervous system chloride transport via gamma-aminobutyric acid (GABAA) related Cl- conductance or Cl-/HCO3- exchange affects anesthetic requirements. To delineate the effects of GABAA-related Cl- conductance blockade versus Cl-/HCO3- exchange inhibition, we determined the change in minimum alveolar anesthetic concentration (MAC) of halothane in rats after intracisternal infusion of 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS). DIDS inhibits Cl-/HCO3- exchange transport in concentrations greater than 1 microM and in GABAA-related Cl- channels in concentrations greater than 0.1 mM. After control MAC determination, rats were given intracisternal mock cerebrospinal fluid (n = 6), 1.0 microM DIDS (n = 8), or 1 mM DIDS (n = 8) at a rate of 2 microL/min for 30 min. Mock cerebrospinal fluid did not change the MAC of halothane. The MAC of halothane increased significantly (P less than 0.001) from 0.96% +/- 0.02% to 1.11% +/- 0.03% (mean value +/- SEM) with 1 microM DIDS and from 0.94% +/- 0.02% to 1.16% +/- 0.04% with 1 mM DIDS. The increases in MAC with 1 microM and 1 mM DIDS were not statistically different. This suggests that Cl-/HCO3- exchange inhibition increases halothane requirements, whereas GABAA-related Cl- channel blockade does not.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1992

Ketorolac does not decrease the MAC of halothane or depress ventilation in rats.

To determine the effects of intravenous (IV) ketorolac on anesthesia and the mechanisms involved, we evaluated its effects on minimum alveolar anesthetic concentration (MAC) and ventilation in halothane-anesthetized rats. Ketorolac in clinical (0.2 and 2 mg/kg) and large (20 and 40 mg/kg) IV doses did not affect the MAC of halothane (0.82% +/- 0.02%). Resting end-tidal CO2 tension (5.1% +/- 0.1%) and the slope of the CO2 response curves (70 +/- 6 mL.min-1.%-1) were also unaffected by IV ketorolac. The mean arterial blood pressure did not significantly change after ketorolac in doses of 0.2, 2, or 20 mg/kg but decreased significantly (P less than 0.05) after 40 mg/kg (placebo 99 +/- 8 mm Hg; ketorolac 87 +/- 6 mm Hg). This study demonstrates that MAC, ventilation, and mean arterial blood pressure are unaffected by clinical doses of IV ketorolac. Furthermore, the lack of effect on MAC and ventilation from larger doses suggests that ketorolac does not have mechanisms of action in the central nervous system.

Analgesics↗
PubMed1991

Transgenic models of tumor development.

Numerous cancer-prone strains of mice have been created by the introduction of candidate tumor-promoting genes into fertilized eggs. Each transgenic strain is predisposed to develop specific types of tumors, but they usually arise stochastically because of the need for spontaneous mutation of genes that collaborate with the introduced oncogene. These mice are providing insights into the effects of individual oncogenes on cellular proliferation, differentiation, and viability, as well as on oncogene cooperativity. Their predisposed state imposes sensitivity to viral and chemical carcinogenesis, and the mice should prove valuable in tests of potential carcinogens, therapies, and preventive measures.

Animals↗
PubMed1991

Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease.

The biological functions of the BCL2 gene were investigated in transgenic mice harboring human BCL2 cDNA under the control of an immunoglobulin heavy chain enhancer (E mu). Mice of a representative transgenic strain, E mu-bcl-2-22, had a great excess of B lymphocytes, immunoglobulin-secreting cells, and serum immunoglobulins, attributable to increased longevity of B-lineage cells. Pre-B and plasma cells as well as B cells exhibited prolonged survival in culture. Immunized animals produced an amplified and protracted antibody response. Within the first year of life, most mice spontaneously produced antibodies to nuclear antigens, and 60% developed kidney disease, diagnosed as immune complex glomerulonephritis. Thus E mu-bcl-2-22 mice constitute a transgenic model for a systemic autoimmune disease resembling the human disorder systemic lupus erythematosus.

Animals↗
PubMed1991

Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice.

To search for genes that can collaborate with myc in lymphomagenesis, we exploited retroviral insertional mutagenesis in E mu-myc transgenic mice. Moloney murine leukemia virus accelerated development of B lymphoid tumors. Three quarters contained a provirus within the known pim-1 or pim-2 loci, new loci bmi-1 and emi-1, or combinations of these. bmi-1 insertions predominated, occurring in half the tumors, and resulted in elevated bmi-1 mRNA levels. Significantly, the bmi-1 gene, which is expressed in diverse normal cells, encodes a Cys/His metal-binding motif (C3HC4) that resembles those in several DNA-binding proteins and defines a new category of zinc finger gene. Thus, myc-induced lymphomagenesis can entail the concerted action of several genes, including the presumptive nuclear regulator bmi-1.

Amino Acid Sequence↗
PubMed1991

A theoretical model of gas transport between arterioles and tissue.

A theoretical model of CO2 and O2 diffusion between arterioles and tissue was developed to determine if significant transport could occur in precapillary vessels. There is increasing evidence, both theoretical and experimental, that such exchange does occur. Using a model in which CO2 and O2 were coupled through the Bohr and Haldane effects, we quantified the radial and axial transport. We also examined the roles of axial diffusion in the arteriole wall and tissue and capillary structure on the transport. Capillary arrangements investigated included capillaries independent of the arteriole with the entering capillary PCO2 or PO2 equal to a constant, and capillaries branching off along the length of the arteriole with the entering capillary partial pressure equal to the arteriole partial pressure at the given axial location. We found that for CO2 in arterioles with an inner diameter ranging from 200 to 22 microns, the exiting blood was 6 to 45% of the way to complete equilibrium with the surrounding tissue, respectively. For O2, the range was 8 to 25%, respectively. We also determined that axial diffusion in the arteriole wall and tissue has little effect on the transport and that capillary structure can alter tissue PCO2 by as much as 12 mm Hg in the smallest arteriole, but has little effect on O2 transport.

Arterioles↗
PubMed1991

Novel murine homeo box gene on chromosome 1 expressed in specific hematopoietic lineages and during embryogenesis.

We describe here a new murine homeo box gene, denoted Hlx, which is expressed within specific hematopoietic lineages. The cDNA sequence indicates that Hlx differs markedly from known vertebrate homeo box genes, and linkage analysis of an interspecific murine backcross showed that it resides at a novel homeo box locus on the distal portion of mouse chromosome 1. The Hlx homeo domain is most similar to that of the Drosophila H2.0 gene, but outside this region the two polypeptides are related only within a few short segments, the most notable being a motif (denoted Hep) also partially conserved in the engrailed and invected homeo proteins and possibly related to an octapeptide in certain paired box proteins. The presence of an intron within the Hlx homeo box at the same position as in several divergent Drosophila genes (H2.0, labial, Distal-less, proboscipedia, Abdominal-B, NK-1) suggests an ancient evolutionary relationship between these genes. RNA analysis of 67 murine hematopoietic cell lines and normal hematopoietic cells revealed Hlx expression throughout the myeloid/macrophage lineage and at early stages of B lymphocyte development but not in T lymphocytes, erythroid cells, or mast cells. Hence, Hlx is a candidate regulator of hematopoietic lineage commitment and maturation. It probably also functions outside the hematopoietic system, however, because Hlx mRNA could be detected in diverse adult tissues and in embryos from as early as day 8 of development.

Amino Acid Sequence↗
PubMed1991

Variable tolerance of the developing follicle and corpus luteum to gonadotropin-releasing hormone antagonist-induced gonadotropin withdrawal in the human.

To examine the differential sensitivity of the ovary to temporary withdrawal of gonadotropin support at different stages of folliculogenesis and corpus luteum function, GnRH antagonist blockade of gonadotropin secretion was examined in 17 studies using the Nal-Glu GnRH antagonist. A vehicle control, antagonist treatment, and follow-up cycle format was used in each study. A previously determined ED100 dose of the Nal-Glu GnRH antagonist (150 micrograms/kg) or vehicle was administered sc every 24 h for 3 consecutive days in the midfollicular phase (MFP), late follicular phase (LFP), and midluteal phase (MLP). In studies in the MFP (n = 7), the largest follicle was 11 +/- 2 mm (mean +/- SEM), and the mean estradiol (E2) level was 220 +/- 44 pmol/L on the first day of antagonist administration. Administration of the antagonist resulted in a 75 +/- 6% suppression of LH (P less than 0.005), no significant change in FSH, and suppression of E2 to the assay detection limit (P less than 0.05). Total cycle length was increased compared to that of the vehicle control cycle (37.3 +/- 1.3 vs. 26.3 +/- 1.1 days; (P less than 0.005) due to prolongation of follicular phase length (P less than 0.005) and reinitiation of folliculogenesis. In the LFP (n = 5), the largest follicle was 16 +/- 1 mm (P less than 0.05 vs. MFP), and the E2 level was 394 +/- 95 pmol/L (P less than 0.05 vs. MFP) on the first day of antagonist administration. Antagonist administration resulted in a 65 +/- 6% suppression of LH (P less than 0.05), a 47 +/- 11% decrease in FSH (P less than 0.05), and no significant change in E2. Total cycle length was prolonged (32.4 +/- 2.2 vs. 25.6 +/- 0.4 days; P less than 0.05) due to an increase in follicular phase length (P less than 0.02); however, the prolongation of the follicular phase was significantly less than that of the MFP (8.0 +/- 1.5 vs. 15.1 +/- 0.1 days; P less than 0.001), suggesting ovulation from the initial dominant follicle. In studies in the MLP (n = 5), LH, E2, and progesterone decreased to the assay detection limit after antagonist administration, while FSH decreased by 36 +/- 4% (P less than 0.05). Menstrual bleeding occurred within 24-48 h of the final Nal-Glu antagonist injection.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1991

Differential expression of the LYL, SCL and E2A helix-loop-helix genes within the hemopoietic system.

The helix-loop-helix genes LYL, SCL and E2A are associated with chromosome translocations found in human lymphoid leukemias. To establish their hematopoietic expression patterns, we have isolated murine LYL and SCL cDNA clones and investigated the expression of all three genes by Northern blot analysis of 58 murine hemopoietic cell lines and tissues. The nucleotide sequences of LYL cDNA clones revealed alternative 5' untranslated sequences and differential splicing within the 5' portion of the coding region that may produce a LYL polypeptide lacking an N-terminal segment. The LYL gene was expressed in most myeloid, erythroid and B lymphocyte cell lines and displayed two alternative size classes of transcripts, the smaller size class (1.5-1.8 kb) being typical of the erythroid lineage and the larger class (2.0-2.3 kb) of the B cell lineage. These two size classes were found to differ in the 5' untranslated region. Thus, expression of the LYL gene appears to be differentially regulated in different hemopoietic cell types. In contrast, the E2A gene was expressed throughout the hemopoietic compartment as a single dominant transcript (3.5 kb). SCL expression was restricted to erythroid, mast and early myeloid cell lines, and the level of SCL transcripts (3.0 and 4.7 kb species) increased markedly during DMSO-induced differentiation of erythro-leukemia cells. Hence the SCL gene product may be an important regulatory factor for the erythroid lineage. The low or undetectable expression of both SCL and LYL in most T lymphoid cell sources is consistent with the view that the translocations of these genes in human T cell leukemias alter their normal regulation and may thereby contribute to neoplasia.

Animals↗
PubMed1990

Inhibiting carbonic anhydrase in brain tissue increases the respiratory response to rebreathing CO2.

To determine the respiratory effects of inhibiting carbonic anhydrase in brain tissue, we infused acetazolamide (ACZ) into the cisterna magna in anesthetized rats. Three concentrations, 4.5, 45 and 450 microM in artificial cerebrospinal fluid, were infused continuously at 2 microliter/min for 20 min and the responses to CO2 rebreathing trials were compared to sham CSF infusions without ACZ. Baseline, steady-state respiration during room air breathing was not affected by these doses of ACZ, but the two higher doses increased the minute ventilation rebreathing response. We conclude that inhibition of carbonic anhydrase in brain tissue increases the respiratory response to rebreathing CO2.

Acetazolamide↗
PubMed1990

An E mu-v-abl transgene elicits plasmacytomas in concert with an activated myc gene.

To clarify how the v-abl oncogene of Abelson murine leukemia virus contributes to lymphoid tumorigenesis, we introduced the gene linked to an immunoglobulin heavy chain enhancer (E mu) into the mouse germline. Although lymphoid development was not detectably affected in young E mu-v-abl mice, three transgenic lines shared a high predisposition to develop clonal plasmacytomas that secreted IgA or IgG. The unexpected absence of pre-B lymphomas suggests that Abelson virus generates such tumors by infecting an early lymphoid progenitor cell that has not yet activated the heavy chain enhancer. Most plasmacytomas bore a rearranged c-myc gene, apparently as a result of spontaneous translocation to the Igh locus. Moreover, progeny of a cross with analogous E mu-myc mice rapidly developed oligoclonal plasmacytomas. Thus, the collusion of v-abl with c-myc is stage specific, efficiently transforming plasma cells but not pre-B cells or B cells.

Abelson murine leukemia virus↗