A non‐peptide compound which can mimic the effect of thrombopoietin via c‐Mpl

Thrombopoietin (TPO) is a cytokine which plays a central role in megakaryopoiesis and platelet production by binding to its cell surface receptor, termed c‐Mpl. In the present study, two benzodiazepinones that compete with the binding of TPO to the extracellular region of c‐Mpl were identified, and one of them stimulated the proliferation of a human TPO‐dependent megakaryocytic cell line, UT‐7/TPO. It stimulated the activation of signal transducer and activator of transcription 5 in UT‐7/TPO cells. These results suggest that a non‐peptide compound can mimic the effect of TPO via c‐Mpl.

[1]  B. Druker,et al.  Recombinant thrombopoietin induces rapid protein tyrosine phosphorylation of Janus kinase 2 and Shc in human blood platelets , 1995 .

[2]  B. Groner,et al.  Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. , 1994, The EMBO journal.

[3]  J. Griffin,et al.  The c-Mpl Ligand (Thrombopoietin) Stimulates Tyrosine Phosphorylation of Jak2, Shc, and c-Mpl (*) , 1995, The Journal of Biological Chemistry.

[4]  D. Goeddel,et al.  Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand , 1994, Nature.

[5]  R. Rees,et al.  Thrombopoietin (TPO) induces tyrosine phosphorylation and activation of STAT5 and STAT3 , 1995, FEBS letters.

[6]  H. Nakauchi,et al.  Establishment and characterization of a human leukemic cell line with megakaryocytic features: dependency on granulocyte-macrophage colony-stimulating factor, interleukin 3, or erythropoietin for growth and survival. , 1991, Cancer research.

[7]  K. Clauser,et al.  Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule. , 1991, Science.

[8]  H. Sadowski,et al.  Cell-free activation of a DNA-binding protein by epidermal growth factor , 1993, Nature.

[9]  C. Papageorgiou,et al.  A non-peptide ligand for the somatostatin receptor having a benzodiazepinone structure , 1996 .

[10]  A. Miyajima,et al.  Receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-5 , 1993 .

[11]  H. Fujita,et al.  Establishment and characterization of an erythropoietin-dependent subline, UT-7/Epo, derived from human leukemia cell line, UT-7. , 1993, Blood.

[12]  H. Anaguchi,et al.  Evidence for the ligand‐induced conversion from a dimer to a tetramer of the granulocyte colony‐stimulating factor receptor , 1994, FEBS letters.

[13]  Y. Watanabe,et al.  Discovery of a novel thrombopoietin mimic agonist peptide. , 1997, Journal of biochemistry.

[14]  J. Johnston,et al.  Thrombopoietin induces tyrosine phosphorylation and activation of the Janus kinase, JAK2. , 1995, Blood.

[15]  L. Giebel,et al.  A sequential dimerization mechanism for erythropoietin receptor activation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[16]  V. Broudy,et al.  Thrombopoietin, the Mp1 ligand, is essential for full megakaryocyte development. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[17]  William Vainchenker,et al.  c-Mpl ligand is a humoral regulator of megakaryocytopoiesis , 1994, Nature.

[18]  A. Gurney,et al.  Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and Shc phosphorylation. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[19]  D. Beeler,et al.  The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[20]  D. Levy,et al.  Thrombopoietin activates a STAT5‐like factor in hematopoietic cells. , 1995, The EMBO journal.

[21]  Ronald W. Barrett,et al.  Small Peptides as Potent Mimetics of the Protein Hormone Erythropoietin , 1996, Science.

[22]  O. Silvennoinen,et al.  Signaling by the cytokine receptor superfamily: JAKs and STATs. , 1994, Trends in biochemical sciences.

[23]  T. Taniguchi.  Cytokine signaling through nonreceptor protein tyrosine kinases. , 1995, Science.

[24]  R. Salgia,et al.  The thrombopoietin receptor c-MPL activates JAK2 and TYK2 tyrosine kinases. , 1995, Experimental hematology.

[25]  M. K. James,et al.  Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity (II): Optimization of the C3 amino substituent. , 1996, Journal of medicinal chemistry.

[26]  M. C. Hu,et al.  Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor MpI , 1994, Cell.

[27]  I. Dusanter-Fourt,et al.  Functional regions of the mouse thrombopoietin receptor cytoplasmic domain: evidence for a critical region which is involved in differentiation and can be complemented by erythropoietin , 1996, Molecular and cellular biology.

[28]  N. Komatsu,et al.  Establishment and characterization of the thrombopoietin-dependent megakaryocytic cell line, UT-7/TPO. , 1996, Blood.

[29]  M. Okuma,et al.  Thrombopoietin, c‐Mpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonists‐induced aggregation in platelets in vitro , 1995, FEBS letters.

[30]  D. Baccanari,et al.  Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine. , 1997, Science.

[31]  S. Goff,et al.  TPO and IL-3 induce overlapping but distinct protein tyrosine phosphorylation in a myeloid precursor cell line. , 1995, Biochemical and biophysical research communications.

[32]  J. Darnell,et al.  Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. , 1994, Science.

[33]  N. Fox,et al.  Thrombopoietin signal transduction in purified murine megakaryocytes. , 1997, Blood.

[34]  J. Mornon,et al.  Molecular cloning and characterization of MPL, the human homolog of the v-mpl oncogene: identification of a member of the hematopoietic growth factor receptor superfamily. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[35]  J. Ihle.  Cytokine receptor signalling , 1995, Nature.

[36]  J. Darnell.  STATs and gene regulation. , 1997, Science.

[37]  M. Uchida,et al.  A Distinct Function of STAT Proteins in Erythropoietin Signal Transduction* , 1997, The Journal of Biological Chemistry.

[38]  B. Druker,et al.  Thrombopoietin induces tyrosine phosphorylation of Stat3 and Stat5 in human blood platelets. , 1996, Blood.

[39]  S. Watson,et al.  Thrombopoietin potentiates activation of human platelets in association with JAK2 and TYK2 phosphorylation. , 1996, The Biochemical journal.

[40]  V. Broudy,et al.  Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin , 1994, Nature.

[41]  Scott R. Presnell,et al.  Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo , 1994, Nature.

[42]  V. Broudy,et al.  Thrombopoietin (c-mpl ligand) acts synergistically with erythropoietin, stem cell factor, and interleukin-11 to enhance murine megakaryocyte colony growth and increases megakaryocyte ploidy in vitro. , 1995, Blood.