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August 1999, Volume 13, Number 8, Pages 1109-1166
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Review
Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs
W L Blalock1, C Weinstein-Oppenheimer1,2, F Chang1, P E Hoyle1, X-Y Wang3, P A Algate4, R A Franklin1,5, S M Oberhaus1,5, L S Steelman1 and J A McCubrey1,5

1Department of Microbiology and Immunology, East Carolina University School of Medicine Greenville, NC, USA

2Escuela de Química y Farmacia, Facultad de Medicina, Universidad de Valparaiso, Valparaiso, Chile

3Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, MN, USA

4Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

5Leo Jenkins Cancer Center, East Carolina University School of Medicine Greenville, NC, USA

Correspondence to: JA McCubrey, Department of Microbiology and Immunology, East Carolina University School of Medicine, Brody Building 5N98C, Greenville, NC 27858, USA; Fax: 252-816-3104

Abstract

Over the past decade, there has been an exponential increase in our knowledge of how cytokines regulate signal transduction, cell cycle progression, differentiation and apoptosis. Research has focused on different biochemical and genetic aspects of these processes. Initially, cytokines were identified by clonogenic assays and purified by biochemical techniques. This soon led to the molecular cloning of the genes encoding the cytokines and their cognate receptors. Determining the structure and regulation of these genes in normal and malignant hematopoietic cells has furthered our understanding of neoplastic transformation. Furthermore, this has allowed the design of modified cytokines which are able to stimulate multiple receptors and be more effective in stimulating the repopulation of hematopoietic cells after myelosuppressive chemotherapy. The mechanisms by which cytokines transduce their regulatory signals have been evaluated by identifying the involvement of specific protein kinase cascades and their downstream transcription factor targets. The effects of cytokines on cell cycle regulatory molecules, which either promote or arrest cell cycle progression, have been more recently examined. In addition, the mechanisms by which cytokines regulate apoptotic proteins, which mediate survival vs death, are being elucidated. Identification and characterization of these complex, interconnected pathways has expanded our knowledge of leukemogenesis substantially. This information has the potential to guide the development of therapeutic drugs designed to target key intermediates in these pathways and effectively treat patients with leukemias and lymphomas. This review focuses on the current understanding of how hematopoietic cytokines such as IL-3, as well as its cognate receptor, are expressed and the mechanisms by which they transmit their growth regulatory signals. The effects of aberrant regulation of these molecules on signal transduction, cell cycle regulatory and apoptotic pathways in transformed hematopoietic cells are discussed. Finally, anti-neoplastic drugs that target crucial constituents in these pathways are evaluated.

Keywords

cytokines; signal transduction; anti-neoplastic drugs; oncogenes; apoptosis

Received 2 March 1999; accepted 14 May 1999
August 1999, Volume 13, Number 8, Pages 1109-1166
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