Possible involvement of bcl-2 in regulation of cell-cycle progression of haemopoietic cells by transforming growth factor-β1
Nadim Mahmud, Naoyuki Katayama, Kazuhiro Nishii, Takayuki Sugawara, Yoshihiro Komada,
Hidetsugu Mitani, Hiroto Araki, Koshi Ohishi, Masato Watanabe, Masahiro Masuya, Masakatsu Nishikawa,
Nobuyuki Minami,
Hideya Ohashi,
Hiroshi Shiku,
Yoshihiro Komada
Department of Paediatrics, Mie University School of Medicine,
Search for more papers by this authorMasakatsu Nishikawa
The Second Department of Internal Medicine,
Search for more papers by this authorNobuyuki Minami
Blood Transfusion Service, Mie University Hospital, Tsu, Mie,
Search for more papers by this authorHideya Ohashi
Pharmaceutical Laboratories, Kirin Brewery Co., Maebashi, Gunma, Japan
Search for more papers by this authorNadim Mahmud, Naoyuki Katayama, Kazuhiro Nishii, Takayuki Sugawara, Yoshihiro Komada,
Hidetsugu Mitani, Hiroto Araki, Koshi Ohishi, Masato Watanabe, Masahiro Masuya, Masakatsu Nishikawa,
Nobuyuki Minami,
Hideya Ohashi,
Hiroshi Shiku,
Yoshihiro Komada
Department of Paediatrics, Mie University School of Medicine,
Search for more papers by this authorMasakatsu Nishikawa
The Second Department of Internal Medicine,
Search for more papers by this authorNobuyuki Minami
Blood Transfusion Service, Mie University Hospital, Tsu, Mie,
Search for more papers by this authorHideya Ohashi
Pharmaceutical Laboratories, Kirin Brewery Co., Maebashi, Gunma, Japan
Search for more papers by this authorDr Naoyuki Katayama The Second Department of Internal Medicine, Mie University School of Medicine. 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
Abstract
Transforming growth factor-β1 (TGF-β1) acts directly on haemopoietic progenitor cells to regulate their growth. To investigate a possible link between the action of TGF-β1 and cell death regulators such as bcl-2, we utilized Ba/F3 cells, the interleukin-3 (IL-3)-dependent growth of which could be modulated by TGF-β1, as well as haemopoietic progenitor cells. We demonstrate here that up-regulation of bcl-2 protein (Bcl-2) as well as that of an inhibitor of cyclin/cyclin-dependent kinase complex, p27, was associated with TGF-β1-induced deceleration of the cell-cycling of haemopoietic progenitor cells and Ba/F3 cells. The data from cell-cycle analysis of Ba/F3 cells showed that TGF-β1 retarded the G1 to S phase transition. Analysis of cells with the potential to express Bcl-2 in an inducible manner indicated that up-regulation of Bcl-2 was sufficient for not only an increase in the level of p27 but also to inhibit the cell growth. Using c-kit-overexpressing cells, we observed that the potential of TGF-β1 to up-regulate the expression of Bcl-2 and p27 could be counteracted by the c-kit ligand, stem cell factor. These results demonstrate that Bcl-2 exerts an essential function in the regulation of G1 to S phase transition of haemopoietic cells by TGF-β1.
References
- 1 Bárcena, A., Park, S.W., Banapour, B., Muench, M.O. & Mechetner, E. (1996) Expression of Fas/CD95 and bcl-2 by primitive hematopoietic progenitors freshly isolated from human fetal liver. Blood, 88, 2013–2025.
- 2 Boise, L.H., González-García, M., Postema, C.E., Ding, L., Lindsten, T., Turka, L.A., Mao, X., Nuñez, G. & Thompson, C.B. (1993) bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell, 74, 597–608.
- 3 Brady, H.J.M., Gil-Gùmez, G., Kirberg, J. & Berns, A.J.M. (1996) Baxα perturbs T cell development and affects cell cycle entry of T cells. EMBO Journal, 15, 6991–7001.
- 4 Campos, L., Rouault, J.-P., Sabido, O., Oriol, P., Roubi, N., Vasselon, C., Archimbaud, E., Magaud, J.-P. & Guyotat, D. (1993) High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood, 81, 3091–3096.
- 5 Campos, L., Sabido, O., Rouault, J.-P. & Guyotat, D. (1994) Effects of BCL-2 antisense oligodeoxynucleotides on in vitro proliferation and survival of normal progenitors and leukemic cells. Blood, 84, 595–600.
- 6 Cardoso, A.A., Li, M.-L., Batard, P., Hatzfeld, A., Brown, E.L., Levesque, J.-P., Sookdeo, H., Panterne, B., Sansilvestri, P., Clark, S.C. & Hatzfeld, J. (1993) Release from quiescence of CD34+ CD38− human umbilical cord blood cells reveals their potentiality to engraft adults. Proceedings of the National Academy of Sciences of the United States of America, 90, 8707–8711.
- 7 Cashman, J.D., Eaves, A.C., Raines, E.W., Ross, R. & Eaves, C.J. (1990) Mechanisms that regulate the cell cycle status of very primitive hematopoietic cells in long-term human marrow cultures. I. Stimulatory role of a variety of mesenchymal cell activators and inhibitory role of TGF-β. Blood, 75, 96–101.
- 8 Chao, D.T., Linette, G.P., Boise, L.H., White, L.S., Thompson, C.B. & Korsmeyer, S.J. (1995) Bcl-xL and Bcl-2 repress a common pathway of cell death. Journal of Experimental Medicine, 182, 821–828.
- 9 Cory, S. (1995) Regulation of lymphocyte survival by the BCL-2 gene family. Annual Review of Immunology, 13, 513–543.
- 10 DeLarco, J.E. & Todaro, G.J. (1978) Growth factors from murine sarcoma virus transformed cells. Proceedings of the National Academy of Sciences of the United States of America, 75, 4001–4005.
- 11 Fairbairn, L.J., Cowling, G.J., Reipert, B.M. & Dexter, T.M. (1993) Suppression of apoptosis allows differentiation and development of a multipotent hemopoietic cell line in the absence of added growth factors. Cell, 74, 823–832.
- 12 Galli, S.J., Zsebo, K.M. & Geissler, E.N. (1994) The c-kit ligand, stem cell factor. Advances in Immunology, 55, 1–96.
- 13 Grzegorzewski, K., Ruscetti, F.W., Usui, N., Damia, G., Longo, D.L., Carlino, J.A., Keller, J.R. & Wiltrout, R.H. (1994) Recombinant transforming growth factor β1 and β2 protect mice from acutely lethal doses of 5-fluorouracil and doxorubicin. Journal of Experimental Medicine, 180, 1047–1057.DOI: 10.1084/jem.180.3.1047
- 14 Hatzfeld, J., Lin, M.-L., Brown, E.L., Sookdeo, H., Levesque, J.-P., O'Toole, T., Gurney, C., Clark, S.C. & Hatzfeld, A. (1991) Release of early human hematopoietic progenitors from quiescence by antisense transforming growth factor β1 or Rb oligonucleotides. Journal of Experimental Medicine, 174, 925–929.DOI: 10.1084/jem.174.4.925
- 15 Hockenbery, D., Nunez, G., Milliman, C., Schreiber, R.D. & Korsmeyer, S.J. (1990) Bcl-2 protein is an inner mitochondrial membrane protein that blocks programmed cell death. Nature, 348, 334–336.DOI: 10.1038/348334a0
- 16 Itoh, R., Katayama, N., Kato, T., Mahmud, N., Masuya, M., Ohishi, K., Minami, N., Miyazaki, H. & Shiku, H. (1996) Activity of the ligand for c-mpl, thrombopoietin, in early haemopoiesis. British Journal of Haematology, 94, 228–235.DOI: 10.1046/j.1365-2141.1996.d01-1814.x
- 17 Jacobsen, F.W., Stokke, T. & Jacobsen, S.E.W. (1995) Transforming growth factor-β potently inhibits the viability-promoting activity of stem cell factor and other cytokines and induces apoptosis of primitive murine hematopoietic progenitor cells. Blood, 86, 2957–2966.
- 18 Katayama, N., Clark, S.C. & Ogawa, M. (1993 a) Growth factor requirement for survival in cell-cycle dormancy of primitive murine lymphohematopoietic progenitors. Blood, 81, 610–616.
- 19 Katayama, N., Shih, J.-P., Nishikawa, S.-i., Kina, T., Clark, S.C. & Ogawa, M. (1993 b) Stage-specific expression of c-kit protein by murine hematopoietic progenitors. Blood, 82, 2353–2360.
- 20 Keller, J.R., Jacobsen, S.E.W., Debois, C.M., Hestdal, K. & Ruscetti, F.W. (1992) Transforming growth factor-β: a bidirectional regulator of hematopoietic cell growth. International Journal of Cell Cloning, 10, 2–11.
- 21 Keller, J.R., Jacobsen, S.E.W., Sill, K.T., Ellingsworth, L.R. & Ruscetti, F.W. (1991) Stimulation of granulopoiesis by transforming growth factor β: synergy with granulocyte/macrophage-colony-stumulating factor. Proceedings of the National Academy of Sciences of the United States of America, 88, 7190–7194.
- 22 Keller, J.R., Mantel, C., Sing, G.K., Ellingsworth, L.R., Ruscetti, S.K. & Ruscetti, F.W. (1988) Transforming growth factor β1 selectively regulates early murine hematopoietic progenitors and inhibits the growth of IL-3-dependent myeloid leukemia cell lines. Journal of Experimental Medicine, 168, 737–750.DOI: 10.1084/jem.168.2.737
- 23 Keller, J.R., McNiece, I.K., Sill, K.T., Ellingsworth, L.R., Quesenberry, P.J., Sing, G.K. & Ruscetti, F.W. (1990) Transforming growth factor β directly regulates primitive murine hematopoietic cell proliferation. Blood, 75, 596–602.
- 24 Kinoshita, T., Yokota, T., Arai, K.-i. & Miyajima, A. (1995) Regulation of Bcl-2 expression by oncogenic Ras protein in hematopoietic cells. Oncogene, 10, 2207–2212.
- 25 Korsmeyer, S.J. (1992) bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood, 80, 879–886.
- 26 Lagasse, E. & Weissman, I.L. (1994) bcl-2 inhibits apoptosis of neutrophils but not their engulfment by macrophages. Journal of Experimental Medicine, 179, 1047–1052.DOI: 10.1084/jem.179.3.1047
- 27 Lee, F., Mulligan, R., Berg, P. & Ringold, G. (1981) Glucocorticoids regulate expression of dihydrofolate reductase cDNA in mouse mammary tumour virus chimaeric plasmids. Nature, 294, 228–232.DOI: 10.1038/294228a0
- 28 Linette, G.P., Li, Y., Roth, K. & Korsmeyer, S.J. (1996) Cross talk between cell death and cell cycle progression: BCL-2 regulates NFAT-mediated activation. Proceedings of the National Academy of Sciences of the United States of America, 93, 9545–9552.DOI: 10.1073/pnas.93.18.9545
- 29 Lisovsky, M., Estrov, Z., Zang, X., Consoli, U., Sanchez-Williams, G., Snell, V., Munker, R., Goodacre, A., Savchenko, V. & Andreeff, M. (1996) Flt3 ligand stimulates proliferation and inhibits apoptosis of acute myeloid leukemia cells: regulation of Bcl-2 and Bax. Blood, 88, 3987–3997.
- 30 Liu, Y.-C., Kawagishi, M., Mikayama, T., Inagaki, M., Takeuchi, T. & Ohashi, H. (1993) Processing of a fusion protein by endoproteinase in COS-1 cells for secretion of mature peptide by using a chimeric expression vector. Proceedings of the National Academy of Sciences of the United States of America, 90, 8957–8961.
- 31 Mahmud, N., Katayama, N., Itoh, R., Ohishi, K., Masuya, M., Minami, N. & Shiku, H. (1996 a) G-CSF accelerates the cell-cycling of hematopoietic progenitor cells and abrogates the deceleration by TNFα. International Journal of Oncology, 8, 453–459.
- 32 Mahmud, N., Katayama, N., Itoh, R., Tanaka, R., Ohishi, K., Masuya, M., Minami, N. & Shiku, H. (1996 b) A possible change in doubling time of haemopoietic progenitor cells with stem cell development. British Journal of Haematology, 94, 242–249.DOI: 10.1046/j.1365-2141.1996.d01-1801.x
- 33 Mazel, S., Burtrum, D. & Petrie, H.T. (1996) Regulation of cell division cycle progression by bcl-2 expression: a potential mechanism for inhibition of programmed cell death. Journal of Experimental Medicine, 183, 2219–2226.DOI: 10.1084/jem.183.5.2219
- 34 Metcalf, D. (1989) The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature, 339, 27–30.DOI: 10.1038/339027a0
- 35 Moore, M.A.S. (1991) Clinical implication of positive and negative hematopoietic stem cell regulators. Blood, 78, 1–19.
- 36 Motoyama, N., Wang, F., Roth, K.A., Sawa, H., Nakayama, K.-i., Nakayama, K., Negishi, I., Senju, S., Zhang, Q., Fujii, S. & Loh, D.Y. (1995) Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science, 267, 1506–1510.
- 37 Ogawa, M. (1993) Differentiation and proliferation of hematopoietic stem cells. Blood, 81, 2844–2853.
- 38 Ohashi, H., Kameda, R., Nishikawa, M., Kawagishi, M. & Liu, Y.-C. (1994) The c-kit receptor transduces the stem cell factor-triggered growth signal in murine interleukin-3-dependent cell line. Cytotechnology, 16, 27–35.
- 39 Ohishi, K., Katayama, N., Itoh, R., Mahmud, N., Miwa, H., Kita, K., Minami, N., Shirakawa, S., Lyman, S.D. & Shiku, H. (1996) Accelerated cell-cycling of hematopoietic progenitors by the flt3 ligand that is modulated by transforming growth factor-β. Blood, 87, 1718–1727.
- 40 Oltvai, Z.N., Milliman, C.L. & Korsmeyer, S.J. (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death. Cell, 74, 609–619.
- 41 Omay, S.B., Nakai, K., Kuno, T., Shiku, H. & Nishikawa, M. (1996) 1α,25-dihydroxyvitamin D3-induced upregulation of calcineurin during leukemic HL-60 cell differentiation. Blood, 87, 2947–2955.
- 42 O'Reilly, L.A., Huang, D.C.S. & Strasser, A. (1996) The cell death inhibitor Bcl-2 and its homologues influence control of cell-cycle entry. EMBO Journal, 15, 6979–6990.
- 43 Palacios, R. & Steinmetz, M. (1985) IL-3-dependent mouse clones that express B-220 surface antigen, contain Ig genes in germ-line configuration, and generate B lymphocytes in vivo. Cell, 41, 727–734.
- 44 Park, J.R., Bernstein, I.D. & Hockenbery, D.M. (1995) Primitive human hematopoietic precursors express Bcl-x but not Bcl-2. Blood, 86, 868–876.
- 45 Ploemacher, R.E., Van Soest, P.L. & Boudewijn, A. (1993) Autocrine transforming growth factor β1 blocks colony formation and progenitor cell generation by hematopoietic stem cells stimulated with steel factor. Stem Cells, 11, 336–347.
- 46 Polyak, K., Lee, M.-H., Erdjument-Bromage, H., Koff, A., Roberts, J.M., Tempst, P. & Massagué, J. (1994) Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell, 78, 59–66.
- 47 Roberts, A.B., Anzano, M.A., Meyers, C.A., Lamb, L.C., Smith, J.M. & Sporn, M.B. (1981) New class of transforming growth factor potentiated by epidermal growth factor: isolation from non-neoplastic tissue. Proceedings of the National Academy of Sciences of the United States of America, 78, 5339–5343.
- 48 Sanz, C., Benito, A., Silva, M., Albella, B., Richard, C., Segovia, J.C., Insunza, A., Bueren, J.A. & Fernández-Luna, J.L. (1997) The expression of Bcl-x is downregulated during differentiation of human hematopoietic progenitor cells along the granulocytic but not the monocyte/macrophage lineage. Blood, 89, 3199–3204.
- 49 Sherr, C.J. & Roberts, J.M. (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes and Development, 9, 1149–1163.
- 50 Tanaka, R., Katayama, N., Ohishi, K., Mahmud, N., Itoh, R., Tanaka, Y., Komada, Y., Minami, N., Sakurai, M., Shirakawa, S. & Shiku, H. (1995) Accelerated cell-cycling of hematopoietic progenitor cells by growth factors. Blood, 86, 73–79.
- 51 Toyoshima, H. & Hunter, T. (1994) p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell, 78, 67–74.
- 52 Vaux, D.L., Cory, S. & Adams, J.M. (1988) bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature, 335, 440–442.DOI: 10.1038/335440a0
- 53 Weber-Nordt, R.M., Henschler, R., Schott, E., Wehinger, J., Behringer, D., Mertelsmann, R. & Finke, J. (1996) Interleukin-10 increases Bcl-2 expression and survival in primary human CD34+ hematopoietic progenitor cells. Blood, 88, 2549–2558.
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