Abstract

The mechanisms underlying the growth of both normal and abnormal (malignant or defective) hematopoiesis have not completely been elucidated. While great strides in the purification of growth factors and some identification of target cells have been accomplished we have yet to determine how molecules are transferred via transmembrane signals to the nuclear machinary which in turn replicates the information of the genome to daughter progeny of hematopoietic stem cells. We have evidence that a macrocyclic lactone family of molecules can stimulate, either directly or via the secondary production of lymphokines by accessory cells, the growth of hematopoietic progenitors. These natural products purified to homogeneity from a marine animal Bugula neritina have the added property of being anti-neoplastic. We plan to determine the functional positive effects of these agents or normal and stem cell defective hematopoietic cells in animals and man and we furthermore will explore the inhibitory effects on tumor cells. Finally, we will attempt to determine the molecular biochemical mechanism of action of these materials on both normal and malignant hematopoietic cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA047993-01
Application #
3191862
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1988-07-01
Project End
1993-05-31
Budget Start
1988-07-01
Budget End
1989-05-31
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Deng, X; Ruvolo, P; Carr, B et al. (2000) Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases. Proc Natl Acad Sci U S A 97:1578-83
Ruvolo, P P; Deng, X; Ito, T et al. (1999) Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A. J Biol Chem 274:20296-300
Ruvolo, P P; Deng, X; Carr, B K et al. (1998) A functional role for mitochondrial protein kinase Calpha in Bcl2 phosphorylation and suppression of apoptosis. J Biol Chem 273:25436-42
Deng, X; Ito, T; Carr, B et al. (1998) Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A. J Biol Chem 273:34157-63
Sharkis, S J; Collector, M I; Barber, J P et al. (1997) Phenotypic and functional characterization of the hematopoietic stem cell. Stem Cells 15 Suppl 1:41-4; discussion 44-5
Ito, T; Deng, X; Carr, B et al. (1997) Bcl-2 phosphorylation required for anti-apoptosis function. J Biol Chem 272:11671-3
May, W S; Tyler, P G; Ito, T et al. (1994) Interleukin-3 and bryostatin-1 mediate hyperphosphorylation of BCL2 alpha in association with suppression of apoptosis. J Biol Chem 269:26865-70
Carroll, M P; May, W S (1994) Protein kinase C-mediated serine phosphorylation directly activates Raf-1 in murine hematopoietic cells. J Biol Chem 269:1249-56
Ito, T; Jagus, R; May, W S (1994) Interleukin 3 stimulates protein synthesis by regulating double-stranded RNA-dependent protein kinase. Proc Natl Acad Sci U S A 91:7455-9
Kennedy, M J; Prestigiacomo, L J; Tyler, G et al. (1992) Differential effects of bryostatin 1 and phorbol ester on human breast cancer cell lines. Cancer Res 52:1278-83

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