We intend to define the structure of the promotor/enhancer subdomains of the PF4 gene and determine the relevance for biologic activity of these regions as well as of any tissue specific factors that might be necessary for gene expression. We hope to examine the effects of Megakaryocyte Stimulatory Factor on the synthesis of PF4 as well as other alpha granule proteins and elucidate the intracellular pathway be which this mediator acts to enhance biosynthesis and/or genetic control of alpha granule proteins that are present within megakaryocytes. We also expect to purify an inhibitor of megakaryocytopoiesis from human platelets, isolate cDNAs which code for the human as well as the rat platelet inhibitor and determine the primary structures of these components. Subsequently, we shall attempt to show that this inhibitor alters the expected bone marrow megakaryocyte parameters as well as the numbers of circulating platelets, and that blocking the action of this protein by immunologic means induces an elevation of the platelet count.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
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Massachusetts Institute of Technology
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Kuter, D J; Rosenberg, R D (1995) The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. Blood 85:2720-30
Ravid, K; Kuter, D J; Rosenberg, R D (1995) rmIL-6 stimulates the transcriptional activity of the rat PF4 gene. Exp Hematol 23:397-401
Aird, W C; Parvin, J D; Sharp, P A et al. (1994) The interaction of GATA-binding proteins and basal transcription factors with GATA box-containing core promoters. A model of tissue-specific gene expression. J Biol Chem 269:883-9
Kuter, D J; Rosenberg, R D (1994) Appearance of a megakaryocyte growth-promoting activity, megapoietin, during acute thrombocytopenia in the rabbit. Blood 84:1464-72
Kuter, D J; Beeler, D L; Rosenberg, R D (1994) The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci U S A 91:11104-8
Ravid, K; Kuter, D J; Beeler, D L et al. (1993) Selection of an HEL-derived cell line expressing high levels of platelet factor 4. Blood 81:2885-90
Ravid, K; Li, Y C; Rayburn, H B et al. (1993) Targeted expression of a conditional oncogene in hematopoietic cells of transgenic mice. J Cell Biol 123:1545-53
Plutzky, J; Neel, B G; Rosenberg, R D (1992) Isolation of a src homology 2-containing tyrosine phosphatase. Proc Natl Acad Sci U S A 89:1123-7
Kuter, D J; Gminski, D M; Rosenberg, R D (1992) Transforming growth factor beta inhibits megakaryocyte growth and endomitosis. Blood 79:619-26
Kuter, D J; Gminski, D; Rosenberg, R D (1992) Botrocetin agglutination of rat megakaryocytes: a rapid method for megakaryocyte isolation. Exp Hematol 20:1085-9

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