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PubMed2005

Acute physical stress elevates mouse period1 mRNA expression in mouse peripheral tissues via a glucocorticoid-responsive element.

In mammals, the circadian and stress systems (both centers of which are located in the hypothalamus) are involved in adaptation to predictable and unpredictable environmental stimuli, respectively. Although the interaction and relationship between these two systems are intriguing and have been studied in different ways since the "pre-clock gene" era, the molecular interaction between them remains largely unknown. Here, we show by systematic molecular biological analysis that acute physical stress elevated only Period1 (Per1) mRNA expression in mouse peripheral organs. Although behavioral rhythms in vivo and peripheral molecular clocks are rather stable against acute restraint stress, the results of a series of promoter analyses, including chromatin immunoprecipitation assays, indicate that a glucocorticoid-responsive element in the Per1 promoter is indispensable for induction of this mRNA both in vitro and in vivo. These results suggest that Per1 can be a potential stress marker and that a third pathway of Per1 transcriptional control may exist in addition to the clock-regulated CLOCK-BMAL1/E-box and light-responsive cAMP-responsive element-binding protein/cAMP-responsive element pathways.

Acute Disease↗
PubMed2003

Differential proteomic analysis of the mouse retina: the induction of crystallin proteins by retinal degeneration in the rd1 mouse.

We have applied proteomic analysis to the degeneration of photoreceptors. In the rd1 mouse, a recessive mutation in the PDE6B gene leads to rapid loss of rods through apoptosis. By 5 wk postnatal, virtually all rod photoreceptors have degenerated, leaving one row of cones that degenerates secondarily. In order to assess comparative protein expression, proteins extracted from whole retina were resolved on a two-dimensional gel and identified by mass spectrometry combined with database screening. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry coupled to peptide mass fingerprinting was sufficient to identify most of the proteins, the remaining being identified with additional sequence information obtained by nano-electrospray ionization tandem mass spectrometry or liquid chromatography tandem mass spectrometry. The study revealed 212 spots, grouped into 109 different proteins. Differential analysis showed loss of proteins involved in the rod-specific phototransduction cascade, as well as induction of proteins from the crystallin family, in response to retinal degeneration. Identification of such pathways may contribute to new therapeutic approaches.

Amino Acid Sequence↗
PubMedDate not supplied

Mouse models incorporating alterations in the major tumor suppressor genes P53 and P16: their use in screening for potential carcinogens, developing further relevant mouse models, and screening for potential chemopreventive and chemotherapetutic agents.

This review is primarily a follow up to an initial review on this subject that the authors published 4 years ago [Lubet et al., Exp Lung Res. 2000; 581-593]. The present review gives a brief discussion of certain background points and rationale for development of these specific models, which had been presented in greater detail in the earlier article. In that initial article the authors identified the potential use of mutant mice in screening for carcinogens as well as preventive or therapeutic agents, discussed the relevance of the dominant-negative P53 mutation, as contrasted with knockout P53 mice, and briefly discussed the pros and cons of mice with a germline mutation in tumor suppressor genes in developing mouse models. The primary objective of the present review is to describe more recent studies using mice the dominant-negative P53 mutation as well as to introduce studies with mice with a heterozygous knockout of the P16/Ink4A ARF locus.

Adenocarcinoma↗
PubMed1992

Oncogenes in X-ray-transformed C3H 10T1/2 mouse cells and in X-ray-induced mouse fibrosarcoma (RIF-1) cells.

In order to better understand the molecular basis of X-ray induced carcinogenesis we have investigated RNA levels of oncogenes in an X-ray transformed C3H 10T1/2 fibroblast line (XTD) and RIF-1 cells isolated from an X-ray-induced fibrosarcoma in a C3H mouse. Steady-state levels of K-ras, H-ras, N-ras, abl, sis, src, and fos were unchanged in the X-ray-transformed cells compared with non-transformed C3H 10T1/2 cells. However, myc and raf mRNA levels were increased dramatically in the transformed cells. Data further suggests a possible alteration in processing of raf RNA in the XTD cells. Southern blot analysis of secondary transfectants induced with XTD DNA indicated that the oncogenic phenotype did not segregate with the myc or raf loci; nor with nine other oncogenes analysed.

Animals↗
PubMed1955

Studies on the immunological response to foreign tumor transplants in the mouse. II. The relation between hemagglutinating antibody and graft resistance in the normal mouse and mice pretreated with tissue preparations.

The relation between serum antibody and resistance to tumor homografts in the mouse has been investigated. Production of serum antibody in response to homografts of a transplantable sarcoma (Sarcoma 1) was demonstrated, by cytotoxic action on the cells of the tumor, and also by a hemagglutinin test. The simpler and more repeatable hemagglutinin test was further investigated. Peak hemagglutinin titres were reached after the immunizing homografts underwent breakdown. Following transfer of lymph node cells from immunized mice into hosts of the same strain, hemagglutinin could be detected in the host serum. The course of its production showed that this secondary antibody was not elicited by transferred antigen, nor could it be due to transfer of preformed antibody. The cells developed the capacity to transfer hemagglutinin production later than the power to transfer heightened graft resistance. Spleen cells also transferred hemagglutinin production, at a later stage after immunization and to a lesser extent than cells from the regional lymph nodes. Implantation of the sarcoma in mice pretreated with certain preparations of lyophilized or frozen tissue stimulated hemagglutinin production, although the tumor grew progressively. The regional lymph nodes participated in the response: they could transfer hemagglutinin production into secondary hosts, but not graft resistance, and indeed appeared to diminish resistance. Lymph node cells from immunized donors conferred protection against the tumor on pretreated mice. Lymph nodes from normal donors also appeared in some experiments to confer protection although the effect was obscured by the rapidity with which the growing tumor became immunologically invulnerable. The fate of lymph node cells stained with acriflavine was followed after transfer. No effect of the staining on the power of the cells to confer immunity could be detected. Cells transferred to the peritoneal cavity passed into various host tissues, but were not found in test homografts. The conclusion is drawn that the hemagglutinating antibody is distinct from the antibody effective in combating homografts. The similarity in this respect between the homograft reaction and sensitization is emphasized in discussion.

Animals↗
PubMed1972

Immune responses in vitro. V. Suppression of M, G, and A plaque-forming cell responses in cultures of primed mouse spleen cells by class-specific antibody to mouse immunoglobulins.

Suppression of Ig class-specific PFC responses by class-specific antibody to mouse immunoglobulin was studied in cultures of spleen cells from immunized mice. In contrast to cultures from normal mice where anti-micro suppressed responses in all Ig classes, anti-micro had progressively less suppressive effect on gamma(1) and gamma(2) responses in cultures from immunized mice with time after immunization. This was most pronounced at 10 days after immunization when anti-micro suppressed gammaM and gammaA responses, but had no or slight effect on gamma(1) or gamma(2) responses which were still suppressed with anti-gamma(1) and anti-gamma(2). These changes in precursor cell susceptibility to anti-micro were antigen specific.

Animals↗
PubMed1959

Protein concentration in normal mouse lymphocytes, thymocytes, and mouse and human leukemic cells as measured by interference microscopy.

The apparent protein content of a single spherical lymphocyte or a similar cell, as well as its diameter, can be measured by a modified and stabilized AO-Baker interference microscope which is either fitted with an AO half-shade eyepiece or connected to a photomultiplier. This paper gives results for the apparent protein content and the diameter of normal mouse lymphocytes and thymocytes; these do not differ significantly from each other. It also gives values for the apparent protein concentration and the diameter of the lymphocytes of mice of the same strain which have developed leukemia or lymphoma; these values are significantly different from those of normal mice. Related data are given for the apparent protein content and for the diameter of normal human lymphocytes and the white cells found in myeloblastic leukemia and in stem cell leukemia in man; here the values differ significantly from those of the normal human lymphocyte. The rule seems to be that the abnormal white cells become more watery and larger as the disease advances.

Animals↗
PubMed2003

Telomere-binding TRF2/MTBP localization during mouse spermatogenesis and cell cycle of the mouse cells L929.

Observations of the organization and distribution of telomeres (Tel) in somatic tissues still remain controversial. The Tel topography revealed by modern microscopy shows them to be associated with the nuclear envelope (NE) in a wide variety of eukaryotic cells, although not at the Rabl orientation (peripheral position at one pole of the nucleus at prophase). We used two cell types that have different nuclear architectures. The cell line L929 shows lack of any rigid Tel architecture in the nucleus. In contrast, spermatozoa have a precise architecture established during spermiogenesis. We observed Tel and membrane Tel binding protein (MTBP/TRF2) position by immunoFISH in L929 cells and by immunofluorescence and immunogold electron microscopy, using antibodies against Membrane Tel Binding Protein (MTBP/TRF2), during different stages of spermiogenesis. At all stages of the L929 cell cycle, MTBP/TRF2 is co-localized with Tel. The only Tel order found in this cell type is similar to the Rabl-orientation, probably due to fast divisions. In the mouse pachytene spermatocytes, the membrane structures abut on the synaptonemal complex (SC) attachment sites contain MTBP/TRF2. In fully formed spermatozoa and during spermiogenesis, apart from the expected MTBP/TRF2 position at the nuclear periphery, MTBP/TRF2 unexpectedly localized at the acrosomal membrane that is adjacent to the nucleus. The difference in the MTBP/TRF2 distribution in the oocyte and spermatozoa leads to the suggestion that the MTBP/TRF2 location might reflect preparation for fertilization events. The Tel distribution is not static in cultured cells throughout the cell cycle or during spermatogenesis. When the Tel are attached to the NE, as during SC formation, MTBP/TRF2 is the member of the protein complex, which appears to be responsible for this attachment.

Animals↗
PubMed2005

Blocking mouse MMP-9 production in tumor cells and mouse cornea by short hairpin (sh) RNA encoding plasmids.

In this study, we assessed the efficacy of the specific knockdown of matrix metalloprotein-9 (MMP-9) in vitro and in vivo using short hairpin RNA (shRNA) against MMP-9. Two plasmids were generated encoding shRNA (pshRNA) targeted against two distinct MMP-9 gene sequences. Transfection of these pshMMP-9s could be shown to specifically inhibit MMP-9 expression both in vivo and in vitro. The effect occurred in vitro both in cells that endogenously produce MMP-9 and in cells exogenously transfected with an MMP-9-encoding plasmid. Using an in vivo transfection approach, the pshMMP- 9 was also effective at inhibiting MMP-9 protein expression in the mouse cornea. pshMMP-9s were also tested against herpes simplex virus (HSV) in the cornea. Delivery of the pshMMP-9 stopped angiogenesis and decreased the severity of herpetic keratitis. However, interferon-alpha (IFN-alpha) and IFN- beta induced by pshRNA might also contribute to inhibition of herpetic simplex keratitis (HSK) in the cornea.

Animals↗
PubMed1995

Characterization of cis-regulatory elements of the c-myc promoter responding to human GM-CSF or mouse interleukin 3 in mouse proB cell line BA/F3 cells expressing the human GM-CSF receptor.

Interleukin 3 (IL-3) or granulocyte macrophage colony-stimulating factor (GM-CSF) activates c-fos, c-jun, and c-myc genes and proliferation in both hematopoietic and nonhematopoietic cells. Using a series of deletion mutants of the beta subunit of human GM-CSF receptor (hGMR) and inhibitors of tyrosine kinase, two distinct signaling pathways, one for activation of c-fos and c-jun genes, and the other for cell proliferation and activation of c-myc gene have been elucidated. In contrast to wealth of information on the pathway leading to activation of c-fos/c-jun genes, knowledge of the latter is scanty. To clarify the mechanisms of activation of c-myc gene by cytokines, we established a transient transfection assay in mouse proB cell line BA/F3 cells expressing hGMR. Analyses of hGMR beta subunit mutants revealed two cytoplasmic regions involved in activation of the c-myc promoter, one is essential and the other is dispensable but enhances the activity. These regions are located at the membrane proximal and the distal regions covering amino acid positions 455-544 and 544-589, respectively. Characterization of cis-acting regulatory elements of the c-myc gene showed that the region containing the P2 promoter initiation site is sufficient to mediate the response to mIL-3 or hGM-CSF. Electrophoretic mobility shift assay using an oligonucleotide corresponding to the distal putative E2F binding site revealed that p107/E2F complex, the negative regulator of E2F, decreased, and free E2F increased after mIL-3 stimulation. These results support the thesis that mIL-3 or hGM-CSF regulates the c-myc promoter by altering composition of the E2F complexes at E2F binding site.

Animals↗
PubMed1981

Tumor promoters induce the synthesis of a secreted glycoprotein in mouse skin and cultured primary mouse epidermal cells.

The effect of tumor promoters and anti-promoters on the synthesis and secretion of a 35,000 mol wt transformation-dependent secreted glycoprotein (MEP) by primary mouse epidermal cells has been investigated. MEP is synthesized and secreted at low levels by cultured epidermal basal cells. The phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) induces a 3-fold increase in the synthesis of MEP as determined by quantitative immunoprecipitation from pulse-labeled cell extracts. This increase is maximal 6 h after treatment and parallels an increase in secretion of MEP measured by appearance of radiolabeled protein in the medium or by radioimmunoassay of culture supernatants. An increase in MEP synthesis is also observed in the skin of mice exposed to TPA. The phorbol ester antagonists retinoic acid, lidocaine and fluocinolone acetonide were examined to determine their effect on the synthesis and secretion of MEP. Of these agents, only fluocinolone acetonide affects MEP levels by suppressing the basal level of MEP synthesis but not its relative induction by TPA. These data suggest that the modifying effects of these three agents on tumor promotion are not mediated via an alteration in MEP synthesis per se is not sufficient for promotion.

Animals↗
PubMed1986

Effect of mouse skin tumor promoters upon [3H]uridine exchange and focus formation in cultures of C3H/10T1/2 mouse fibroblasts.

The abilities of 4-O-methyl-12-O-tetradecanoylphorbol-13-acetate (4-O-methyl-TPA) and mezerein to promote the process of transformation were evaluated in cultures of C3H/10T1/2 mouse embryo fibroblasts treated with N-methyl-N'-nitro-N-nitrosoguanidine. Mezerein was found to be as potent as the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) for the promotion of focus formation, eliciting a promotion response at concentrations that ranged from 100 to 2500 ng/ml. 4-O-Methyl-TPA (25-2500 ng/ml) did not promote focus formation, but was mitogenic for confluent cultures. The effects of promoting and non-promoting compounds upon intercellular communication were then evaluated to determine if a rapid assay for the inhibition of communication might serve as a surrogate for the relatively long term, labor-intensive cell transformation assay. Inhibited intercellular communication, as measured by inhibition of [3H]uridine exchange between cells, appeared to correlate with the ability of phorbol related compounds to promote transformation. However, the potent promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin did not inhibit [3H]uridine transfer. Inhibition of intercellular communication may thus be diagnostic of the promoting potential of phorbol-related compounds in C3H/10T1/2 cultures, but may not be an appropriate endpoint for the study of carcinogenic dioxins.

Animals↗
PubMed1996

In vitro immunization of naive mouse B cells: establishment of IgM secreting hybridomas specific for souble protein or hapten from B cells cultured on CD40 ligand transfected mouse fibroblasts.

CD40 has been shown to play an important role in the regulation of B cell survival, proliferation and Ig class switching. The natural partner for CD40 is CD40 ligand, gp 39, which is transiently expressed on activated T cells. In vitro, CD40 ligation leads to polyclonal B cell proliferation and, in the presence of appropriate cytokines, to the secretion of Ig of various isotypes. In the present study we show that naive B cells cultured in vitro on CD40L-transfected mouse fibroblasts in the presence of two different soluble antigens (beta-galactosidase and phenyloxazolone coupled to ovalbumin) can be specifically immunized as shown by direct single cell Elispot assays or after establishment of B cell hybridomas. However, under the conditions of in vitro immunization used, all hybridomas analysed produced specific IgM antibodies only and we failed to detect cells that had switched to other isotypes. The data suggests that CD40 ligation can be used for efficient in vitro immunization against soluble antigens for IgM production but that CD40 signals even in conjunction with cytokines are insufficient to induce high rate switching.

Animals↗
PubMed1987

Modulation of the transferred mouse 26K casein gene in mouse L cells by glucocorticoid hormone.

The cloned 26K casein gene was transferred to mouse L-cells and its expression was measured by Northern blot hybridization. When the lambda clone with 5'- and 3'-flanking sequences was transferred, transcripts were detected without glucocorticoid, but in the presence of glucocorticoid, the level of the transcripts of heterogeneous sizes increased and their pattern was similar to that observed in the mammary glands of non-lactating mice. When the 6.7 kb EcoRI fragment containing most of the coding region was transferred, putative precursor and mature mRNAs were detected without glucocorticoid. Surprisingly, with the addition of glucocorticoid, the level of the transcripts greatly decreased. The presence of multiple sequences responsible for glucocorticoid receptor binding was detected in the 5'-flanking region of the gene in a competition assay using the subfragments of casein gene and on sequence analysis. These results suggest that the 26K casein gene has multiple regulatory domains which interact with glucocorticoid receptors, and these domains may play different roles in the regulation of the casein gene.

Animals↗
PubMed1987

A mouse monoclonal antibody to human alpha 2-macroglobulin (alpha 2M) crossreacts with alpha 2M from mouse: epitope mapping and characterization of subunit structure of murine alpha 2M.

Mice were immunized with the isolated C-terminal heat-induced fragment of human alpha 2-macroglobulin (alpha 2M) and the spleens were used to prepare hybridomas. A monoclonal antibody (Mab) designated F17D5 was selected for further characterization. The epitope defined by Mab F17D5 was not expressed on alpha 2M, on alpha 2M-methylamine, or on alpha 2M-proteinase complexes. On the other hand, the antibody reacted avidly with denatured human alpha 2M and with some types of alpha 2M from other species, including mouse, on nitrocellulose-immunoblotting. The epitope of Mab F17D5 was mapped to less than 250 residues C-terminal of the internal thiolester of human alpha 2M. This was based on CNBr fragmentation of the 60 kDa C-terminal heat-fragment and on peptide mapping of alpha 2M, derivatized at the internal thiolester GLX-residue with 125I-labeled histamine. Murine alpha 2M was confirmed to contain two types of subunit: a 185 kDa subunit and a combination of 165 kDa and 35 kDa polypeptides. By partial disulfide bond reduction, heat-fragmentation and immunoblotting with Mab F17D5, the structure of murine alpha 2M was compared to that of human alpha 2M. The F17D5-epitope was mapped to a 30 kDa heat-induced fragment, which was released by denaturation without reduction. This fragment contained an intrachain disulfide bridge. By analogy with human alpha 2M, the 35 kDa subunit would be located at the C-terminal end of murine alpha 2M, disulfide-bonded to the major 165 kDa subunit.

Animals↗
PubMed1990

Clearance of desialylated mouse alpha-macroglobulin and murinoglobulin in the mouse.

Mouse alpha-macroglobulin and murinoglobulin were labeled with 125I and utilized for plasma clearance studies performed with mice. Desialylated murinoglobulin was rapidly cleared from the circulation with a half-life of about 5 min. On the other hand, desialylated alpha-macroglobulin showed a biphasic curve: about half was cleared at a rate similar to that of the intact molecule while the remaining half had a shorter half-life of about 20 min which was prolonged by a simultaneous injection of a 200-fold excess of unlabeled asialoorosomucoid. Virtually no cross competition was observed between these asialoglobulins and formaldehyde-treated bovine serum albumin or trypsin-bound alpha-macroglobulin. These results suggest that the intravascular elimination of desialylated alpha-macroglobulin and murinoglobulin is independent of the clearance systems responsible for formaldehyde-modified proteins or proteinase-bound alpha-macroglobulins, and that the structure or spatial arrangement, or both, of oligosaccharide units of alpha-macroglobulin is somewhat different from that of murinoglobulin, resulting in a difference of avidity of interaction with the asialoglycoprotein receptor. The desialylated alpha-macroglobulin and murinoglobulin accumulated principally in the liver.

Animals↗
PubMed1994

Use of the translational mobility of a plasma membrane protein to assess fertilization of mouse oocytes and viability of mouse zygotes and two-cell embryos.

The fluorescence photobleaching recovery (FPR) technique was used to measure the translational mobility of a glycoprotein recognized by the monoclonal antibody (mAb) S75 in plasma membranes of mouse oocytes, zygotes, and two-cell embryos. Glycoprotein fractional mobility (f) was significantly decreased in membranes of unfertilized oocytes compared to zygotes or two-cell embryos (f values, 46 +/- 2 and 65 +/- 2%, respectively; p < 0.0001). Reduced apparent glycoprotein mobility was also observed in morphologically degenerated zygotes and two-cell embryos compared to viable zygotes and two-cell embryos (f values, 8 +/- 1 and 60 +/- 3%, respectively; p < 0.0001). These results indicate that the FPR technique can be used to assess oocyte fertilization and preimplantation embryonic viability. This method may be useful in the evaluation of embryonic viability following in vitro fertilization and in the detection of toxic effects of novel compounds on embryonic development.

Animals↗
PubMed2001

Offspring from normal mouse oocytes injected with sperm heads from the azh/azh mouse display more severe sperm tail abnormalities than the original mutant.

Sperm with abnormalities in the position and shape of the head were obtained from the azh/azh mutant and injected into the cytoplasm of mature mouse oocytes to determine whether sperm from the offspring display both head (club shape) and tail (looping, folding, and fusion) abnormalities observed in the mutant donor. Although quantitative differences were observed among the three examined offspring, we found that abnormalities in sperm head shape were less frequent than in the donor mutant, but that tail malformations predominated. In addition, we found that the frequency of tail abnormalities increased during sperm epididymal transit. A typical defect was the multiple folding of the sperm tail and eventual fusion of closely apposed plasma membranes. As a consequence, sperm forward motility and natural fertility were compromised. Results of this study indicate that the azh/azh mutant and offspring generated by intracytoplasmic sperm injection provide a valuable model for determining the role of the manchette and keratin-containing outer dense fibers and fibrous sheath during spermiogenesis. Furthermore, our findings stress the risk of enhancing a phenotypic abnormality caused by mutant male genotypes introduced through bypassing the biologic mechanisms of natural sperm selection during fertilization.

Animals↗