Abstract

The overall goal is to define cellular and molecular mechanisms involved in the modulation of normal and neoplastic hematopoiesis. Studies will be pursued on the mechanism of action of erythroid-potentiating activity (EPA), the physiology of GM-CSF in humans, and the interaction of polypeptide growth hormones with normal and malignant hematopoietic cells. Radioimmunoassays will be developed for EPA and CSF. These hemopoietins have been molecularly cloned and are expressed in mammalian cells. The purified and recombinant proteins will be used to develop antibodies for the radioimmunoassays which will be applied to normals and to patients with various disorders of hematopoiesis for the purpose of defining the physiologic and pathophysiologic role of these hemopoietic regulators in man. The EPA receptor will be purified and antibodies developed against it. Its amino terminus sequence will be determined in order to construct oligonucleotide probes to molecularly clone the human gene for the EPA receptor. EPA receptor clones will be used to predict the structure and sequence of the receptor protein and to examine its organization in genomic DNA. Also, expression of receptor RNA will be studied by Northern analysis in various and malignant cell types. The interaction of specific polypeptide hormones with normal and malignant hematopoietic cells will be investigated in depth with respect to the mechanism of action of EPA at the cellular level and the action of growth hormone, insulin, and insulin growth factors on hemic cells. Permanent human T-lymphoid cell lines will be developed using the human T-leukemia viruses to transform cells from appropriate patients in order the examine the genetic or epigenetic basis of hormonal resistance and to define the underlying mechanism thereof. These studies should provide important insights regarding the role of various hemopoietins in normal and malignant hematopoiesis in man and define the basis of polypeptide growth hormone action on hemic cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA030388-13
Application #
3482184
Study Section
Special Emphasis Panel (NSS)
Project Start
1981-07-01
Project End
1993-12-31
Budget Start
1992-01-01
Budget End
1992-12-31
Support Year
13
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Dhar-Mascareno, Manya; Mascareno, Eduardo; Golde, David W (2009) Early signaling by vascular endothelial growth factor and placental growth factor in human bone marrow-derived endothelial cells is mediated by superoxide. J Vasc Res 46:601-8
Heaney, Mark L; Gardner, Jeffrey R; Karasavvas, Nicos et al. (2008) Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res 68:8031-8
Perez-Cruz, Isabel; Carcamo, Juan M; Golde, David W (2007) Caspase-8 dependent TRAIL-induced apoptosis in cancer cell lines is inhibited by vitamin C and catalase. Apoptosis 12:225-34
K C, Sagun; Carcamo, Juan M; Golde, David W (2006) Antioxidants prevent oxidative DNA damage and cellular transformation elicited by the over-expression of c-MYC. Mutat Res 593:64-79
Chen, Jian; Carcamo, Juan M; Golde, David W (2006) The alpha subunit of the granulocyte-macrophage colony-stimulating factor receptor interacts with c-Kit and inhibits c-Kit signaling. J Biol Chem 281:22421-6
Dhar-Mascareno, Manya; Pedraza, Alicia; Golde, David W (2005) PI3-kinase activation by GM-CSF in endothelium is upstream of Jak/Stat pathway: role of alphaGMR. Biochem Biophys Res Commun 337:551-6
KC, Sagan; Carcamo, Juan M; Golde, David W (2005) Vitamin C enters mitochondria via facilitative glucose transporter 1 (Glut1) and confers mitochondrial protection against oxidative injury. FASEB J 19:1657-67
Dhar-Mascareno, Manya; Carcamo, Juan M; Golde, David W (2005) Hypoxia-reoxygenation-induced mitochondrial damage and apoptosis in human endothelial cells are inhibited by vitamin C. Free Radic Biol Med 38:1311-22
DeYulia Jr, Garrett J; Carcamo, Juan M; Borquez-Ojeda, Oriana et al. (2005) Hydrogen peroxide generated extracellularly by receptor-ligand interaction facilitates cell signaling. Proc Natl Acad Sci U S A 102:5044-9
Araten, David J; Golde, David W; Zhang, Rong H et al. (2005) A quantitative measurement of the human somatic mutation rate. Cancer Res 65:8111-7

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