Signal transduction, cell cycle regulatory, and anti-apoptotic pathways regulated by IL-3 in hematopoietic cells: possible sites for intervention with anti-neoplastic drugs

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.

The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1

“…32 However, bone marrow MNCs from Gfi1 ϩ/ϩ , Gfi1 ϩ/Ϫ , and Gfi1 Ϫ/Ϫ mice similarly activated Erk1/2 phosphorylation with 10 ng/mL IL-3 ( Figure 2A), which was a stronger activator of Erk1/2 than G-CSF ( Figure 2B), presumably reflective of the wider expression of IL-3-responsive cells in bone marrow MNCs.…”

Alteration of Akt activity increases chemotherapeutic drug and hormonal resistance in breast cancer yet confers an achilles heel by sensitization to targeted therapy

“…The PI3K/PTEN/Akt/mTOR and Raf/MEK/ERK pathways are also activated by many growth factors and cytokines which are important in driving proliferation and preventing apoptosis of breast cells (Blalock et al, 1999, McCubrey et al, 2005. After growth receptor ligation, Shc, a Src homology (SH)-2 (SH2)-domain containing protein, becomes associated with the c-terminus of the growth factor receptor (Matsuguchi et al, 1994, Inhorn et al, 1995, Okuda et al, 1999.…”

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

“…The IL-3 and GM-CSF genes located on the 5q region of chromosome 5 has been associated with hematopoietic malignancies, underlining the importance of these cytokines in hematopoietic signaling (Blalock et al, 1999). The receptors for these cytokines have unique ligand binding-alpha chains and share the common beta (gp140) signal transducing subunit (Itoh et al, 1990;Murata et al, 1992;Gearing et al, 1989;Hayashida et al, 1990).…”

“…This chimeric receptor promoted di erentiation in response to IL-3, elucidating the role of the a subunit in conferring speci®city and determining cell fate via distinct signal transduction events. For a detailed characterization of regions on the a and b c chains responsible for interaction with other signal transduction molecules, regulation of gene expression, DNA synthesis, proliferation, di erentiation and apoptosis, readers are referred to a recent review on the topic and references therein (Blalock et al, 1999).…”