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1.
J Cell Biol ; 151(6): 1169-78, 2000 Dec 11.
Article in English | MEDLINE | ID: mdl-11121433

ABSTRACT

Microtubule-associated proteins such as MAP1B have long been suspected to play an important role in neuronal differentiation, but proof has been lacking. Previous MAP1B gene targeting studies yielded contradictory and inconclusive results and did not reveal MAP1B function. In contrast to two earlier efforts, we now describe generation of a complete MAP1B null allele. Mice heterozygous for this MAP1B deletion were not affected. Homozygous mutants were viable but displayed a striking developmental defect in the brain, the selective absence of the corpus callosum, and the concomitant formation of myelinated fiber bundles consisting of misguided cortical axons. In addition, peripheral nerves of MAP1B-deficient mice had a reduced number of large myelinated axons. The myelin sheaths of the remaining axons were of reduced thickness, resulting in a decrease of nerve conduction velocity in the adult sciatic nerve. On the other hand, the anticipated involvement of MAP1B in retinal development and gamma-aminobutyric acid C receptor clustering was not substantiated. Our results demonstrate an essential role of MAP1B in development and function of the nervous system and resolve a previous controversy over its importance.


Subject(s)
Brain/pathology , Cell Communication/physiology , Corpus Callosum/pathology , Microtubule-Associated Proteins/genetics , Nerve Tissue Proteins/genetics , Peripheral Nervous System/pathology , Animals , Axons/physiology , Brain/embryology , Corpus Callosum/embryology , Genes, Lethal , Heterozygote , Homozygote , Mice , Mice, Mutant Strains , Myelin Sheath/pathology , Peripheral Nervous System/embryology , Receptors, GABA/isolation & purification , Retina/embryology , Sequence Deletion
2.
FEBS Lett ; 451(1): 15-8, 1999 May 14.
Article in English | MEDLINE | ID: mdl-10356975

ABSTRACT

The microtubule-associated proteins 1B and 1A are synthesized as polyprotein precursors which are rapidly cleaved to give rise to heavy and light chains constituting the respective microtubule-associated protein 1B or microtubule-associated protein 1A complex. To identify domains necessary for precursor processing, we expressed microtubule-associated protein 1B deletion mutants in fibroblasts and monitored proteolytic cleavage of the precursor proteins by immunoblot analysis. We found that a novel hydrophilic, proline-rich 45 amino acid domain containing the cleavage site is necessary and sufficient for processing. This domain is conserved in microtubule-associated protein 1A. Additional sequences in the N-terminal half of the heavy chain contribute to the efficiency of cleavage.


Subject(s)
Microtubule-Associated Proteins/metabolism , Protein Precursors/metabolism , Protein Processing, Post-Translational , Proteins/metabolism , 3T3 Cells , Amino Acid Sequence , Animals , Binding Sites , Endopeptidases/metabolism , Humans , Mice , Microtubule-Associated Proteins/genetics , Molecular Sequence Data , Protein Precursors/genetics , Proteins/genetics , Rats , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Sequence Homology, Amino Acid
3.
Biochim Biophys Acta ; 1445(3): 345-50, 1999 Jun 09.
Article in English | MEDLINE | ID: mdl-10366719

ABSTRACT

We determined the previously unknown 3' end of MAP1B mRNA. We found an unusually long and highly conserved 3' untranslated region (3'UTR) of 4.3 kb and detected a polymorphism in the 3' flanking region probably due to the integration of an endogenous retroviral MuERV-L element. Furthermore, we found that MAP1B 3'UTR overlapped with the 5' end of the cDNA encoding DBI-1. However, further analysis suggested that the published structure of DBI-1 cDNA is most likely the result of fortuitous joining of unrelated cDNA fragments during cloning.


Subject(s)
Microtubule-Associated Proteins/genetics , Receptors, Cell Surface/genetics , Untranslated Regions/genetics , Animals , Brain/embryology , Brain/metabolism , DEAD-box RNA Helicases , DNA, Complementary/chemistry , Exons , Mice , Molecular Sequence Data , RNA-Binding Proteins , Sequence Homology , Tumor Suppressor Proteins , Untranslated Regions/chemistry
4.
Biochim Biophys Acta ; 1444(2): 299-305, 1999 Feb 16.
Article in English | MEDLINE | ID: mdl-10023088

ABSTRACT

Ataxin-3 is a protein of unknown function which is mutated in Machado-Joseph disease by expansion of a genetically unstable CAG repeat encoding polyglutamine. By analysis of chicken ataxin-3 we were able to identify four conserved domains of the protein and detected widespread expression in chicken tissues. In the first such analysis in a non-primate species we found that in contrast to primates, the chicken CAG repeat is short and genetically stable.


Subject(s)
Nerve Tissue Proteins/genetics , Amino Acid Sequence , Animals , Ataxin-3 , Base Sequence , Cell Line , Chickens , Conserved Sequence , DNA, Complementary/genetics , DNA, Complementary/isolation & purification , Female , Gene Expression , Machado-Joseph Disease/genetics , Molecular Sequence Data , Nerve Tissue Proteins/chemistry , Nuclear Proteins , Peptides/chemistry , Peptides/genetics , Repressor Proteins , Sequence Homology
5.
J Cell Biol ; 143(3): 695-707, 1998 Nov 02.
Article in English | MEDLINE | ID: mdl-9813091

ABSTRACT

Previous studies on the role of microtubule-associated protein 1B (MAP1B) in adapting microtubules for nerve cell-specific functions have examined the activity of the entire MAP1B protein complex consisting of heavy and light chains and revealed moderate effects on microtubule stability. Here we have analyzed the effects of the MAP1B light chain in the absence or presence of the heavy chain by immunofluorescence microscopy of transiently transfected cells. Distinct from all other MAPs, the MAP1B light chain-induced formation of stable but apparently flexible microtubules resistant to the effects of nocodazole and taxol. Light chain activity was inhibited by the heavy chain. In addition, the light chain was found to harbor an actin filament binding domain in its COOH terminus. By coimmunoprecipitation experiments using epitope-tagged fragments of MAP1B we showed that light chains can dimerize or oligomerize. Furthermore, we localized the domains for heavy chain-light chain interaction to regions containing sequences homologous to MAP1A. Our findings assign several crucial activities to the MAP1B light chain and suggest a new model for the mechanism of action of MAP1B in which the heavy chain might act as the regulatory subunit of the MAP1B complex to control light chain activity.


Subject(s)
Microtubule-Associated Proteins/metabolism , 3T3 Cells , Actins/metabolism , Amino Acid Sequence , Animals , Cell Line , Endopeptidases/metabolism , Mice , Microtubule-Associated Proteins/genetics , Microtubules/physiology , Molecular Sequence Data , PC12 Cells , Rats
6.
Genomics ; 49(3): 430-6, 1998 May 01.
Article in English | MEDLINE | ID: mdl-9615228

ABSTRACT

We report the genomic organization of the mouse and rat genes coding for the 2460-amino-acid microtubule-associated protein (MAP) 1B. In addition to seven exons that encode full-length MAP1B, we have identified two alternative exons, exon 3A and the novel exon 3U. We demonstrate that alternative MAP1B transcripts containing either exon 3A or exon 3U are expressed in a variety of mouse and rat tissues at about 1 to 10% of the level of regular transcripts. The alternative transcripts, if translated, would give rise to MAP1B isoforms truncated at the N-terminus. The exon/intron organization underlying the alternative transcripts and the N-terminal amino acid sequence of the putative truncated MAP1B isoforms resemble those of MAP1A, providing further evidence for an evolutionary relationship. The detection of alternative transcripts has implications for the interpretation of conflicting results recently obtained in MAP1B knockout mice.


Subject(s)
Alternative Splicing , Genome , Mice/genetics , Microtubule-Associated Proteins/biosynthesis , Microtubule-Associated Proteins/genetics , Transcription, Genetic , Animals , Base Sequence , Exons , Glioma , Humans , Infant, Newborn , Introns , Mice, Knockout , Microtubule-Associated Proteins/chemistry , Molecular Sequence Data , Organ Specificity , Polymerase Chain Reaction , Rats , Sequence Alignment , Sequence Homology, Nucleic Acid , Tumor Cells, Cultured
7.
FEBS Lett ; 423(2): 254-8, 1998 Feb 20.
Article in English | MEDLINE | ID: mdl-9512368

ABSTRACT

Recently, the concept of microtubule-associated protein 1B as an intracellular 2460 amino acid protein was challenged by the suggestion that only the N-terminal 1022 codons are utilized and encode the core protein of the extracellular proteoglycan claustrin (Burg and Cole (1994) J. Neurobiol. 25, 1-22). We expressed this N-terminal MAP1B fragment in tissue culture cells and found that it bound to microtubules and was not localized in the extracellular matrix. In addition, epitope mapping demonstrated that MAP1B consisted of more than 1022 amino acids and that the reported cDNA of claustrin is incomplete.


Subject(s)
Chondroitin Sulfate Proteoglycans/genetics , Keratan Sulfate/genetics , Microtubule-Associated Proteins/genetics , Proteoglycans/genetics , 3T3 Cells , Animals , Brain/cytology , Chondroitin Sulfate Proteoglycans/chemistry , Keratan Sulfate/chemistry , Lumican , Mice , Microtubule-Associated Proteins/chemistry , Microtubule-Associated Proteins/physiology , Microtubules/metabolism , Rats , Tumor Cells, Cultured/metabolism
8.
Oncogene ; 14(25): 3017-27, 1997 Jun 26.
Article in English | MEDLINE | ID: mdl-9223665

ABSTRACT

Serum deprived v-mos-transformed NIH3T3 cells are unable to enter a true quiescent state, but instead, arrest in the early G1 phase of the cell cycle. We have analysed several cell cycle regulatory proteins in these G1 arrested cells and show altered regulation in the expression and activity of certain cyclins and cyclin-dependent kinases. In particular, p34cdc2, cyclin A, cyclin D and cyclin E are not appropriately down-regulated in serum starved, G1 arrested, v-mos-transformed cells as compared with quiescent NIH3T3 cells. Furthermore, serum starved v-mos-transformed cells have elevated histone H1 kinase activity associated with cyclin A, cyclin E, p33cdk2, and p34cdc2. Using a metallothionein-inducible c-mos(mu) expression system, we show that c-mos(mu) induction in quiescent NIH3T3 cells causes elevated expression of p34cdc2. However, this induction of c-mos(mu) and subsequent expression of p34cdc2 was not sufficient to promote significant entry of cells into S phase. Analysis of extracts from serum starved v-H-ras, v-src, and tpr-met transformed NIH3T3 cells demonstrates that these oncogene-transformed cells also contain elevated levels of p34cdc2. We propose that the altered regulation of these critical cell cycle regulatory molecules, and specifically the inability to fully downregulate their activity, contributes significantly to neoplastic transformation and subsequent unregulated growth of tumor cells.


Subject(s)
CDC2-CDC28 Kinases , Cyclin-Dependent Kinases/metabolism , Cyclins/metabolism , Down-Regulation , Genes, mos , 3T3 Cells/physiology , 3T3 Cells/virology , Animals , CDC2 Protein Kinase/genetics , CDC2 Protein Kinase/metabolism , Cell Division/genetics , Cell Line, Transformed , Culture Media, Serum-Free , Cyclin D1 , Cyclin-Dependent Kinase 2 , G1 Phase/genetics , Metallothionein/genetics , Mice , Oncogene Proteins/metabolism , Oncogenes , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism
9.
Genes Dev ; 11(23): 3143-56, 1997 Dec 01.
Article in English | MEDLINE | ID: mdl-9389647

ABSTRACT

Previous studies suggest that plectin, a versatile cytoskeletal linker protein, has an important role in maintaining the structural integrity of diverse cells and tissues. To establish plectin's function in a living organism, we have disrupted its gene in mice. Plectin (-/-) mice died 2-3 days after birth exhibiting skin blistering caused by degeneration of keratinocytes. Ultrastructurally, hemidesmosomes and desmosomes appeared unaffected. In plectin-deficient mice, however, hemidesmosomes were found to be significantly reduced in number and apparently their mechanical stability was altered. The skin phenotype of these mice was similar to that of patients suffering from epidermolysis bullosa simplex (EBS)-MD, a hereditary skin blistering disease with muscular dystrophy, caused by defects in the plectin gene. In addition, plectin (-/-) mice revealed abnormalities reminiscent of minicore myopathies in skeletal muscle and disintegration of intercalated discs in heart. Our results clearly demonstrate a general role of plectin in the reinforcement of mechanically stressed cells. Plectin (-/-) mice will provide a useful tool for the study of EBS-MD, and possibly other types of plectin-related myopathies involving skeletal and cardiac muscle, in an organism amenable to genetic manipulation.


Subject(s)
Heart/physiology , Intermediate Filament Proteins/physiology , Muscle, Skeletal/physiology , Skin Physiological Phenomena , Animals , Animals, Newborn , Cell Line , Desmosomes , Disease Models, Animal , Epidermolysis Bullosa Simplex/etiology , Epidermolysis Bullosa Simplex/genetics , Female , Gene Deletion , Heart Defects, Congenital/etiology , Heart Defects, Congenital/genetics , Humans , Intermediate Filament Proteins/deficiency , Intermediate Filament Proteins/genetics , Keratinocytes/cytology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Knockout , Muscle, Skeletal/abnormalities , Muscle, Skeletal/ultrastructure , Myocardium/ultrastructure , Plectin , RNA, Messenger , Skin Abnormalities/etiology , Skin Abnormalities/genetics , Skin Abnormalities/pathology
10.
Neurobiol Aging ; 17(2): 235-41, 1996.
Article in English | MEDLINE | ID: mdl-8744404

ABSTRACT

Transgenic mice expressing the oncogenic protein-serine/threonine kinase Mos at high levels in the brain display progressive neuronal degeneration and gliosis. Gliosis developed in parallel with the onset of postnatal transgene expression and led to a dramatic increase in the number of astrocytes positive for GFAP, vimentin, and possibly tau. Interestingly, vimentin is normally expressed only in immature or neoplastic astrocytes, but appears to be induced to high levels in Mos-transgenic, mature astrocytes. Mos can activate mitogen activated protein kinase (MAPK) and MAPK has been implicated in Alzheimer-type tau phosphorylation. In the Mos-transgenic brain we found increased levels of phosphorylation at one epitope on tau containing serines 199 and 202 (numbering according to human tau), a pattern similar but not identical to that found in Alzheimer's disease. In addition, Mos-transgenic mice express a novel neurofilament-related protein that might be a proteolytic neurofilament heavy chain degradation product. These results suggest that activation of protein phosphorylation in neurons can result in changes in cytoskeletal proteins that might contribute to neuronal degeneration.


Subject(s)
Nerve Degeneration/physiology , Neurofilament Proteins/metabolism , Oncogene Proteins v-mos/metabolism , tau Proteins/metabolism , Animals , Brain Chemistry/genetics , Epitopes/genetics , Female , Glial Fibrillary Acidic Protein/metabolism , Gliosis/pathology , Humans , Immunoblotting , Immunohistochemistry , Male , Mice , Mice, Transgenic , Phosphorylation , RNA, Messenger/biosynthesis , Vimentin/biosynthesis , Vimentin/genetics
11.
Cell Growth Differ ; 6(3): 325-36, 1995 Mar.
Article in English | MEDLINE | ID: mdl-7794800

ABSTRACT

To explore the role of pp39mos in male germ cell meiosis, we have constructed transgenic mice carrying either the c-Mos or v-Mos genes linked to the human male germ cell-specific phosphoglycerate kinase-2 promoter. All male transgenic mice bearing the v-Mos but not the c-Mos construct were sterile due to arrest of germ cells at metaphase I. Immunocytochemistry performed on sections from control and c-Mos transgenic testes with eight different monoclonal and polyclonal antisera against either alpha-, beta- or gamma-tubulins demonstrated that all could recognize MI spermatocyte spindles from control and c-Mos transgenics, but only one monoclonal anti-microtubule sera decorated the spindles of v-Mos-arrested meiotic figures. Western blot analyses with this one serum revealed a change in proteins in the v-Mos samples. Immunocytochemistry with the MPM-2 monoclonal antibody, which is specific for epitopes phosphorylated during mitosis, demonstrated an increase in cytoplasmic and spindle-associated phosphoproteins in arrested v-Mos spermatocytes. Western analysis with MPM-2 showed an increase in a M(r) 50,000-55,000 and a M(r) 25,000-29,000 protein in Mos transgenic testes when compared to controls. An anti-MAP kinase antibody demonstrated an increase in all four MAP kinases in testes of transgenic mice. Thus, overexpression of pp39v-mos during male germ cell meiosis resulted in an alteration of various cell cycle related kinases and cytostatic factor-like arrest at MI.


Subject(s)
Oncogene Proteins v-mos/biosynthesis , Proto-Oncogene Proteins c-mos/biosynthesis , Spermatozoa/physiology , Animals , Base Sequence , Humans , Infertility, Male/etiology , Male , Meiosis , Metaphase , Mice , Mice, Transgenic , Microtubules/metabolism , Molecular Sequence Data , Oncogene Proteins v-mos/genetics , Oncogene Proteins v-mos/toxicity , Phosphoglycerate Kinase/biosynthesis , Phosphoglycerate Kinase/genetics , Phosphoproteins/biosynthesis , Protein Serine-Threonine Kinases/biosynthesis , Proto-Oncogene Proteins c-mos/genetics , Spermatozoa/cytology , Testis/metabolism , Testis/pathology , Testis/ultrastructure
12.
Oncogene ; 10(4): 623-30, 1995 Feb 16.
Article in English | MEDLINE | ID: mdl-7862439

ABSTRACT

The Mos protein kinase is a serine-/threonine-specific protein kinase with a crucial role in meiotic cell divisions in vertebrates. Several oncogenic derivatives of the c-Mos protein have been discovered in murine retroviruses. These proteins have acquired mutations and exhibit different degrees of protein kinase activity in vitro. In an attempt to understand the factors governing Mos protein kinase activity we have compared the kinase activities of the wild-type c-Mos protein and two v-Mos proteins (strain HT1 and MSV124) after expression in insect cells. Only the 124 v-Mos protein showed kinase activity in vitro as measured by autophosphorylation, vimentin phosphorylation or by phosphorylation and activation of MAP kinase kinase. By domain swapping and site-directed mutagenesis we identified a single point mutation in the 124 v-Mos protein (Arg145-->Gly) which is responsible for its constitutive activity. This residue is located in the alpha-helix C of the kinase domain close to the ATP binding fold and is conserved in all known c-Mos proteins. Introduction of the corresponding mutation into HT1 v-Mos and into murine c-Mos activated both proteins for autophosphorylation, vimentin phosphorylation and for signalling via MAP kinase kinase in vitro. We hypothesize that the Arg145-->Gly mutation found in 124 v-Mos mimicks a conformational change which might be an obligatory step in the activation of c-Mos in vivo.


Subject(s)
Oncogene Proteins v-mos/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-mos/metabolism , Amino Acid Sequence , Animals , Arginine/chemistry , Base Sequence , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , DNA Primers/chemistry , Glycine/chemistry , Mice , Molecular Sequence Data , Mutagenesis, Site-Directed , Phosphorylation , Protein Conformation , Recombinant Proteins , Signal Transduction , Structure-Activity Relationship , Vimentin/metabolism
13.
Exp Cell Res ; 213(1): 210-7, 1994 Jul.
Article in English | MEDLINE | ID: mdl-8020593

ABSTRACT

The product of the mos protooncogene normally functions in the induction of meiosis and regulation of cell-cycle progression in oocytes. Here we have investigated the cell-cycle progression of NIH3T3 cells transformed by the v-mos gene. Flow cytometric analysis showed that logarithmically growing v-mos-transformed cells do not differ from their nontransformed counterparts in the distribution of cells in the G1, S, and G2/M phases. Likewise, after serum withdrawal for 48 h, both normal and v-mos-transformed NIH3T3 cells have essentially ceased proliferation, as analyzed by flow cytometry, [3H]thymidine and BrdU incorporation into newly synthesized DNA, and mitotic indexes. However, while the normal NIH3T3 cells are arrested in a quiescent state, the v-mos-transformed cells are arrested in early to mid G1, prior to the point where cells require certain amino acids for proliferation (V point). In agreement with these different arrest points, the v-mos-transformed cells enter S phase following serum stimulation within about 8 h, without the additional 4- to 6-h lag period characteristically displayed by the parental NIH3T3 cells. In addition, we show a lack of expression of a growth arrest-specific gene product, gas1, in the serum-arrested v-mos-transformed cells. These data demonstrated that v-mos-transformed cells display growth characteristics that differ fundamentally from those of normal cells or cells transformed by overexpression of myc [1]. Our results suggest that the v-mos oncoprotein transforms cells, at least in part, by preventing exit from the cell cycle into quiescence.


Subject(s)
Cell Cycle/genetics , Genes, mos , Moloney murine sarcoma virus/genetics , 3T3 Cells , Animals , Cell Division/genetics , Cell Line , Culture Media , Culture Media, Serum-Free , DNA Replication , Fluorescent Antibody Technique , G1 Phase/genetics , Gene Expression , Kinetics , Mice , Protein Biosynthesis , Proteins/analysis , Time Factors , Virus Integration
14.
Exp Cell Res ; 202(1): 199-202, 1992 Sep.
Article in English | MEDLINE | ID: mdl-1511734

ABSTRACT

We have investigated the mRNA expression of the Ets-1 and Ets-2 genes in murine gonads and found expression in adult ovaries. In situ hybridization experiments show that the Ets genes are predominantly expressed in theca cells and cells of ovarian interstitium. By gel retardation experiments we detected DNA binding proteins in ovaries that specifically bind to the ETS motif, suggesting the expression of Ets or Ets-related proteins. Our results raise the possibility of Ets-2 involvement in ovarian pathology seen in patients with Down's syndrome.


Subject(s)
Protein-Tyrosine Kinases/biosynthesis , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogenes , Repressor Proteins , Theca Cells/physiology , Trans-Activators , Transcription Factors , Animals , Base Sequence , Blotting, Northern , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/isolation & purification , Female , Gene Expression , Mice , Mice, Inbred BALB C , Molecular Sequence Data , Oligodeoxyribonucleotides , Oligonucleotides, Antisense , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Protein c-ets-1 , Proto-Oncogene Protein c-ets-2 , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-ets , RNA, Messenger/analysis , RNA, Messenger/biosynthesis , Thymus Gland/physiology
15.
J Neuropathol Exp Neurol ; 51(5): 499-505, 1992 Sep.
Article in English | MEDLINE | ID: mdl-1381415

ABSTRACT

To study the function of the protooncogene Mos in mouse brain development we have created a transgenic mouse model system in which an activated form of the gene, the murine retroviral v-Mos gene, is highly overexpressed in the brain. Six transgenic founder animals and mice of one established transgenic line (line TG66) displayed a progressive hind limb paralysis with onset between 18 days and 9 months. The severity of the neurological phenotype correlated with pathological alterations and the degree of v-Mos expression in the brain which varied between individual animals of line TG66. The most striking feature of the brain pathology was the presence of large, abnormal astrocytes in the cerebellum, medulla, thalamus and in the dorsal horn of the spinal cord. These areas also contained shrunken and basophilic neurons whose cytoplasm was abnormally immunoreactive for phosphorylated epitopes of neurofilaments. In addition to neuropathologic changes, these mice also displayed aberrant eye lens differentiation and absence of hair cells in the inner ear. These results establish v-Mos transgenic mice as a model system to study progressive neurodegenerative disease and provide further evidence that the Mos protein-serine/threonine kinase has a function in brain development.


Subject(s)
Genes, mos , Hindlimb , Mice, Transgenic/genetics , Paralysis/genetics , Animals , Brain/metabolism , Central Nervous System/pathology , Mice , Paralysis/pathology , Paralysis/physiopathology , Phenotype , RNA/metabolism
16.
Int J Cancer ; 51(2): 310-4, 1992 May 08.
Article in English | MEDLINE | ID: mdl-1568797

ABSTRACT

Transgenic mice carrying the mouse mos proto-oncogene linked to a retroviral LTR develop hyperplasia of the Harderian glands. Enlargement of the glands is evident as early as 18 weeks after birth, with glands reaching up to 10 times their normal weight. Approximately 65% of the cases of hyperplasia occur bilaterally, and the majority of mice affected are male (66%). Elevated levels of mos expression are found in all Harderian glands of mice from the affected transgenic line, but not in glands of normal mice or a non-affected transgenic line, indicating that hyperplasia is dependent on mos expression. Histological examination of the tissue reveals a general involvement of the entire gland epithelium in hyperplastic growth, with no evidence of focal or malignant tumours. These observations show that in addition to neu, myc, ras and ret transgenes, mos, a member of the protein-serine/threonine kinase family of oncogenes, can induce Harderian gland hyperplasia, thus revealing an unusual response by this organ to various classes of oncogenes. Analysis of fos, jun, myc and ets oncogene RNA in mos-induced hyperplastic Harderian glands shows that there are no consistent changes in the level of expression of these oncogenes, suggesting that mos acts via a mechanism other than by increasing the expression of these genes.


Subject(s)
Genes, mos , Harderian Gland/pathology , Animals , Exophthalmos/etiology , Genes, mos/genetics , Hyperplasia/complications , Hyperplasia/genetics , Mice , Phenotype , RNA, Messenger/analysis
17.
Henry Ford Hosp Med J ; 40(3-4): 307-11, 1992.
Article in English | MEDLINE | ID: mdl-1362427

ABSTRACT

We have previously described a neurological phenotype for transgenic mice carrying the c-Mos proto-oncogene. Pheochromocytomas and C-cell thyroid neoplasms occur in these transgenic lines in patterns that are similar to those seen in multiple endocrine neoplasia type 2 (MEN 2). Characterization of the pathological lesions via immunohistochemistry underscores similarities between MEN 2 and these transgenic mice. When transgenic mice that do not display the MEN 2 phenotype are crossed to a different background, the progeny display the MEN 2 phenotype. Thus the interaction of the background with the transgene is such that it can suppress tumor information. This observation bears special relevance to the human syndrome in that this model system may be used to study the question of penetrance of phenotype.


Subject(s)
Disease Models, Animal , Mice, Transgenic , Multiple Endocrine Neoplasia/pathology , Adrenal Gland Neoplasms/genetics , Adrenal Gland Neoplasms/pathology , Animals , Carcinoma/genetics , Carcinoma/pathology , Mice , Mice, Transgenic/genetics , Multiple Endocrine Neoplasia/genetics , Pheochromocytoma/genetics , Pheochromocytoma/pathology , Proto-Oncogene Mas , Proto-Oncogene Proteins/genetics , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology
18.
Cancer Res ; 52(2): 450-5, 1992 Jan 15.
Article in English | MEDLINE | ID: mdl-1345812

ABSTRACT

Transgenic mice carrying and expressing a mos protooncogene, linked to the Moloney murine sarcoma virus long terminal repeat, develop severe neurological defects and lens abnormalities. Here we report that after long latent periods, mice in three of four of these mos transgenic lines develop a high frequency of multicentric pheochromocytomas and/or medullary thyroid neoplasms. The pattern of tumor formation is remarkably similar to the human autosomal dominantly inherited neoplastic syndrome, multiple endocrine neoplasia type 2 (MEN 2), and tumors from these transgenic animals display the same neuroendocrine marker staining pattern as seen in MEN 2. The similarity between the tumor pathologies and presentation patterns of MEN 2 patients and mos transgenic mice suggests that they may arise through related pathways. The type of tumor presentation varies in a line-dependent manner indicating that there is interaction between the transgene and the genetic background. Moreover, when the non-tumor-bearing mos transgenic line is crossed to a different mouse background, the F1 offspring display the MEN 2 phenotype. These studies indicate that penetrance of the autosomal dominant mos transgenic phenotype is dependent on both integration site and background.


Subject(s)
Genes, mos , Multiple Endocrine Neoplasia/genetics , Neoplasms, Experimental/pathology , Pheochromocytoma/genetics , Thyroid Neoplasms/genetics , Adrenal Gland Neoplasms/genetics , Animals , Blotting, Northern , Disease Models, Animal , Gene Expression , Mice , Mice, Transgenic , RNA, Messenger/genetics
19.
Proc Natl Acad Sci U S A ; 87(24): 9703-7, 1990 Dec.
Article in English | MEDLINE | ID: mdl-1702218

ABSTRACT

Independent transgenic mouse lines carrying the mouse Mos protooncogene linked to a retroviral transcriptional control sequence display behavioral abnormalities including circling, head tilting, and head bobbing. This dominant phenotype shows various degrees of penetrance in different transgenic founder animals and lines. Neuronal and axonal degeneration, gliosis, and inflammatory infiltrates are found in all transgenic mouse lines in which behavioral traits are present. Recordings of auditory-evoked potentials in mice of one of these lines demonstrate that transgenic mice are deaf; in these mice spiral ganglia degenerate and most of the cochlear hair cells are absent. By using an S1 nuclease protection assay, we have detected RNA expression of the transgene in all tissues examined and, in particular, at high levels in brain. In situ hybridization experiments show that Mos expression can be detected in specific areas of the central nervous system. Lesions are present in areas with demonstrable overexpression of Mos.


Subject(s)
Brain/pathology , Nervous System Diseases/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogenes , Transcription, Genetic , Animals , Female , Hair Cells, Auditory/pathology , Inflammation , Mice , Mice, Inbred Strains , Mice, Transgenic , Nervous System Diseases/pathology , Neurons/pathology , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins c-mos , RNA/genetics , RNA/isolation & purification
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