Abstract
In order to reveal cellular processes sensitive to abnormal c-myb expressionin vivo, transgenic mice were produced by introducing the c-myb nuclear proto-oncogene under the ubiquitous transcriptional regulatory unit of the cytoplasmic β-actin gene. Expression of c-myb in thymus did not cause apparent abnormality, but the mice unexpectedly developed degenerative abnormalities in skeletal and cardiac muscles; this occurred predominantly in males. Expression of c-myb in skeletal muscle was correlated with an inflammation of muscle and was accompanied by vacuolar degeneration of muscle fibres, their regeneration, and lymphocyte infiltration. The identical pathological progression in cardiac muscle was associated with cardiomegaly.
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Alitalo, K., Winqvist, R., Lin, C., Chapelle, A. de la, Schwab, M., and Bishop, J.M. (1984) Aberrant expression of an amplified c-myb oncogene in two cell lines from a colon carcinoma.Proc. Natl Acad. Sci. USA 81, 4534–8.
Banker, B.Q., and Engel, A.G. (1986) The polymyositis and dermatomyositis syndromes. In Engel, A.G. and Banker, B.Q., eds,Myology pp. 1385–421. McGraw-Hill.
Behringer, R.R., Peschon, J.J. Messing, A., Gartside, C.L., Hanschka, C.L., Palmiter, R.D. and Brinster, R.L. (1988) Heart and bone tumours in transgenic mice.Proc. Natl Acad. Sci. USA 85, 2648–52.
Biedenkapp, H., Borgmeyer, U., Sippel, A.E., and Klempnauer, K.-H. (1988) Viralmyb oncogene encodes a sequence-specific DNA-binding activity.Nature 335, 835–7.
Blau, H.M. (1988) Hierarchies of regulatory genes may specify mammalian development.Cell 53, 673–4.
Bugaisky, L. and Zak, R. 1984. Biological mechanisms of hypertrophy. In Fozzard, H., Haber, E., Jennings, R., Katz, A. and Morgan, H., eds,The Heart and Cardiovascular System, pp. 1491–1506. New York: Scientific Foundation, Raven Press.
Chirgwin, J., Aeylye, A., McDonald, R. and Ruther, W. (1979) Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease.Biochemistry 18, 5294–9.
Clarke, M.F., Kukowska-Latallo, J.F., Westin, E., Smith, M. and Prochownik, E.W. (1988) Constitutive expression of a c-myb cDNA blocks Friend murine erythroleukemia cell differentiation.Mol. Cell. Biol. 8, 884–92.
Clubb, F.J. and Bishop, S.P. (1984) Formation of binucleated mycocardial cells in the neonatal rat. An index for growth hypertrophy.Lab Invest. 50, 571–7.
Colmenares, C. and Stavnezer, E. (1989) Theski oncogene induces muscle differentiation in quail embryo cells.Cell 59, 293–303.
Duprey, S.P. and Boettiger, D. (1985) Developmental regulation of c-myb in normal myeloid progenitor cells.Proc. Natl Acad. Sci. USA 82, 6937–41.
Falcone, G., Tato, F. and Alema, S. (1985) Distinctive effects of the viral oncogenesmyc, erb, fps, andsrc on the differentiation program of quail myogenic cells.Proc. Natl Acad. Sci. USA 82, 426–30.
Fields, L.J. (1988) Atrial natriuretic factor-SV40 T antigen transgenes produce tumors and cardiac arrhythmias in mice.Science 239, 1029–32.
Forster, G., Bernt, E. and Bergmeyer, H.U. (1974) Creatine kinase. In Bergmeyer, H.E., ed.,Methods of Enzymatic Analysis, pp. 784–97.
Gewirts, A.M. and Calabretta, B. (1988) A c-myb antisense oligodeoxynucleotide inhibits normal human hematopoiesisin vitro.Science 242, 1303–6.
Gewitz, A.M., Anfossi, G., Venturelli, D. Valpreda, S., Sins, R. and Calabretta, B. (1989) G1/S transition in normal human T-lymphocytes requires the nuclear protein encoded by c-myb.Science 245, 80–183.
Glisin, V., Crkvenjakov, R. and Byus, C. (1974) Ribonucleic acid isolated by cesium chloride centrifugation.Biochemistry 13, 2633–7.
Gonda, T.J., Shieness, D.K., and Bishop, J.M. (1982) Transcripts from the cellular homologs of retroviral oncogenes: distribution among chicken tissues.Mol. Cell Biol. 2, 617–24.
Gonda, T.J. and Metcalf, D. (1984) Expression ofmyb, myc andfos proto-oncogenes during differentiation of a murine myeloid leukemia.Nature 310, 249–51.
Gonda, T.J., Gough, N.M., Dunn, A.R. and Blaquiere, J. (1985) Nucleotide sequence of cDNA clones of the murinemyb proto-oncogene.EMBO J. 4, 2003–8.
Griffin, C. and Baylin, S. (1985) Expression, of the c-myb oncogene in human small cell lung carcinoma.Cancer Res. 45, 272–5.
Haupt, H.M. and Grover, M.H. (1982) The heart and cardiac conduction system in polymyositis-dermatomyositis: a clinicopathologic study of 16 autopsied patients.Am. J. Cardiol. 50, 998–1006.
Hill, D.L. and Barrows, H.S. (1968) Identical skeletal and cardiac muscle involvement in a case of fatal polymyositis.Arch. Neurol. 19, 545–51.
Introna, M., Golay, J., Frampton, J., Nakano, T., Ness, S.A. and Frag, T. (1990) Mutations in v-myb alter the differentiation of myelomonocytic cells transformed by the oncogene.Cell 63, 1287–97.
Izumo, S., Nadal-Ginard, B. and Mahdavi, V. (1988) Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload.Proc. Natl Acad. Sci. USA 85, 339–43.
Jackson, T., Allard, M.F., Sreenan, C.M., Doss, L.K., Bishop, S.P. and Swain, J.L. (1990) The c-myc proto-oncogene regulates cardiac development in transgenic mice.Mol. Cell. Biol. 10, 3709–16.
Klempnauer, K.-H., Gonda, T.J. and Bishop, J.M. (1982) Nucleotide sequence of the retroviral leukemia gene v-myb and its cellular progenitor c-myb: the architecture of a transduced oncogene.Cell 31, 453–63.
Komuro, I., Kurabayashi, M., Takaku, F. and Yazaki, Y. (1988) Expression of cellular oncogenes in the myocardium during the developmental stage and pressure-overloaded hypertrophy of the rat heart.Circu. Res. 62, 1075–9.
Lassar, A.B., Thayer, M.J., Overell, R.W. and Weintraub, H. (1989) Transformation by activatedras orfos prevents myogenesis by inhibiting expression of myoD1.Cell 58, 659–67.
Lehrach, H., Diamond, K., Wozney, J.M. and Boedtker, H. (1977) RNA molecular weight determinations by gel electrophoresis under denaturating conditions, a critical reexamination.Biochemistry 16, 4743–51.
Massague, J., Cheifetz, S., Endo, T. and Nadal-Ginard, B. (1986) Type β transforming growth factor is an inhibitor of myogenic differentiation.Proc. Natl Acad. Sci. USA 83, 8206–10.
Mastaglia, F.L. and Kakulas, B.A. (1970) A histological and histochemical study of skeletal muscle regeneration in polymyositis.J. Neurol. Sci. 10, 471–87.
Mayer, Y., Czosnek, H., Zeelon, P.E., Yaffe, D. and Nudel, Y. (1984) Expression of the genes coding for the skeletal and cardiac actions in the heart.Nucl. Acids Res. 12, 1087–100.
McKnight, G.S. (1978) The induction of ovalubumin and coalbumin mRNA by estrogen and progesterone in chick oviduct explant cultures.Cell 14, 403–13.
Moscovici, C. and Gazzolo, L. (1982) Transformation of hemopoietic cells with avian leukemia viruses.Adv. Viral Oncol. 1, 83–106.
Mucenski, M.L., McLain, K., Kier, A.B., Swerdlow, S.H., Schreiner, C.M., Miller, T.A., Pietryga, D.W., Scott, W.J. Jr. and Potter, S.S. (1991) A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis.Cell 65, 677–89.
Nakagoshi, H., Nagase, T., Ueno, Y. and Ishii, S. (1989) Transcriptionaltrans-repression by the c-myb proto-oncogene product.Nucl. Acids Res. 17, 7315–24.
Nakagoshi, H., Nagase, T., Kanei-Ishii, C., Ueno, Y. and Ishii, S. (1990) Binding of the c-myb proto-oncogene product to the simian virus 40 enhancer stimulates transcription.J. Biol. Chem. 265, 3479–83.
Nishina, Y., Nakagoshi, H., Imamoto, F., Gonda, T.J. and Ishii, S. (1989) Trans-activation by the c-myb proto-oncogene.Nucl. Acids Res. 17, 107–17.
Ness, S.A., Marknell, A. and Graf, T. (1989) The v-myb oncogene product binds to and activates the promyelocyte-specificmim-1 gene.Cell 59, 1115–25.
Oh-ishi, M. and T. Hirabayashi (1988) Micro-two-dimensional gel electrophoresis with agarose gel in the first dimension.Physico-Chemical Biology 32, 1–8.
Olson, E.N., Spizz, G. and Tainsky, M.A. (1987) The oncogenic forms of N-ras or H-ras prevent skeletal myoblast differentiation.Mol. Cell. Biol. 7, 2104–11.
Radke, K., Beug, H., Kornfeld, S. and Graf, T. (1982) Transformation of both erythroid and myeloid cells by E26, an avian leukemia virus that contains themyb gene.Cell 31, 643–53.
Rushlow, K.E., Lautenberger, J.A., Papas, T., Baluda, M.A., Perbal, B., Chrikjian, J.G. and Reddy, E.P. (1982) Nucleotide sequence of the transforming gene of avian myeloblastosis virus.Science 216, 1421–3.
Ruther, U., Wagner, E.F. and Muller, R. (1985) Analysis of the differentiation-promoting potential of inducible c-fos genes introduced into embryonal carcinoma cells.EMBO J. 4, 1775–81.
Sakura, H., Kanei-Ishii, C., Nagase, T., Nakagoshi, H., Gonda, T.J. and Ishii, S. (1989) Delineation of three functional domains of the transcriptional activator encoded by the c-myb proto-oncogene.Proc. Natl Acad. Sci. USA 86, 5758–62.
Saule, S., Merigaud, J.P., Al-Moustafa, A.-E.M., Ferre, F., Rong, P.M., Amouyel, P.B., Quatannens, D., Stehelin, D. and Dieterlen-Lievre, F. (1987) Heart tumors specifically induced in young avian embryos by the v-myc oncogene.Proc. Natl Acad. Sci. USA 84, 7982–6.
Seiler-Tuyns, A., Eldridge, J.D. and Paterson, B.M. (1984) Expression and regulation of chicken actin genes introduced into mouse myogenic and non-myogenic cells.Proc. Natl Acad. Sci. USA 81, 2980–4.
Slamon, D., de Kernion, J., Verma, I. and Cline, M. (1984) Expression of cellular oncogenes in human malignancies.Science 224, 256–62.
Southern, E.M. (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis.J. Mol. Biol. 98, 503–17.
Stern, J.B. and Smith, K.A. (1986) Interleukin-2 induction of T-cell G1 progression and c-myb expression.Science 233, 203–6.
Suda, Y., Aizawa, S., Hirai, S., Inoue, T., Fruta, Y., Suzuki, M., Hirohasi, S. and Ikawa, Y. (1987) Driven by the same Ig enhancer and SV40 T promoterras induced lung adenomatous tumors,myc induced pre-B cell lymphomas and SV40 large T gene a variety of tumors in transgenic mice.EMBO J. 6, 4055–65.
Suda, Y., Aizawa, S., Fruta, Y., Yagi, T., Ikawa, Y., Saitoh, K., Yamada, Y., Toyoshima, K. and Yamamoto, T. (1990) Induction of a variety of tumors by c-erb B2 and clonal nature of lymphomas even with the mutated gene (Val659-Glu659).EMBO J. 9, 181–90.
Sutrave, P., Copeland, T.D., Showalter, S.D. and Hughes, S.H. (1990a) Characterization of chicken c-ski oncogene products expressed by retroviral vectors.Mol. Cell Biol. 10, 3137–44.
Sutrave, P., Kelly, A. M. and Hughes, S.H. (1990b)ski can cause selective growth of skeletal muscle in transgenic mice.Genes Dev. 4, 1462–72.
Swynghedauw, B. (1986) Developmental and functional adaptation of contractile proteins in cardiac and skeletal muscles.Physiol. Rev. 66, 710–71.
Thiele, C., McKeon, C., Ross, R., Reynolds, C. and Israel, M. (1987) Differential proto-oncogene expression characterizes histopathologically indistinguishable tumors of the peripheral nervous system.J. Clin. Invest. 80, 804–11.
Thompson, C., Challoner, P., Neiman, P. and Groudine, M. (1986) Expression of the c-myb proto-oncogene during cellular proliferation.Nature 319, 374–80.
Todokoro, K., Watson, R.J., Higo, H., Amanuma, H., Kuramochi, S., Yanagisawa, H. and Ikawa, Y. (1988) Down-regulation of c-myb gene expression is a prerequisite for erythropoietin-induced erythroid differentiation.Proc. Natl Acad. Sci. USA 85, 8900–4.
Webster, K.A., Muscat, G.E.O. and Kedes, L. (1988) Adenovirus E1A products suppress myogenic differentiation and inhibit transcription from muscle-specific promoters.Nature 332, 553–7.
Westin, E.H., Gallo, R.C., Arya, S.K., Eva, A., Souza, L.M., Baluda, M.A., Aaronson, S.A. and Wong-Staal, F. (1982) Differential expression of themyb gene in human hematopoietic cells.Proc. Natl Acad. Sci. USA 79, 2194–8.
Weston, K. and Bishop, J.M. (1989) Transcriptional activation by the v-myb oncogene and its cellular progenitor, c-myb.Cell 58, 85–93.
Yee, S.-P., Mock, D., Maltby, V., Silver, M., Rossant, J., Bernstein, A. and T. Pawson, (1989) Cardiac and neurological abnormalities in v-fps transgenic mice.Proc. Natl Acad. Sci. USA 86, 5873–7.
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Furuta, Y., Aizawa, S., Suda, Y. et al. Degeneration of skeletal and cardiac muscles in c-myb transgenic mice. Transgenic Research 2, 199–207 (1993). https://doi.org/10.1007/BF01977350
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DOI: https://doi.org/10.1007/BF01977350