title: E2F1 promotes cytokine mediated cell survival via a mechanism that is separable from its cell cycle regulatory effects.
abstract: Cytokines are important regulators of lymphocyte proliferation and survival during immune responses. The retinoblastoma pathway constitutes an important intracellular network that forms the basis of cell cycle regulation and cellular proliferation in all mammalian cells. Transcription factors of the E2F family form a central component of this pathway, and represent important targets for activation by mitogenic cytokines such as interleukin-2 (IL-2). We have previously described a model for study of the E2F1 transcription factor by stable overexpression in the cytokine-dependent lymphoid progenitor cell line BaF-B03. In this model of IL-2 receptor signalling, E2F1 overexpressing BaF-B03 cells exhibit cytokine-independent cellular proliferation and survival, thereby supporting the concept that E2F activation is a critical step in the genesis of clonal expansion of antigen-primed lymphocytes. Here, we provide evidence linking E2FI to a serum-dependent cell survival pathway that is separable from its cell cycle regulatory effects. Our data show that the serum glycerophospholipid lysophosphatidic acid is capable of mediating this survival effect via a mechanism that is sensitive to chemical inhibition of phosphatidylinositol 3-kinase. IL-2 mediated cell survival, but not cell cycle progression, is dependent upon this serum-dependent cell survival pathway. The findings presented here provide an insight into how mitogenic cytokines such as IL-2 regulate the apparently separate processes of lymphocyte proliferation and survival via recruitment of the retinoblastoma pathway.
authors.affiliation: Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, New South Wales, Australia.
authors.forename: Salvador
authors.initials: S
authors.lastname: Gala
authors.forename: Peter
authors.initials: P
authors.lastname: Williamson
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D044967:Serum / Q000737:chemistry; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004791:Enzyme Inhibitors; D006133:Growth Substances; D007376:Interleukin-2; D008246:Lysophospholipids; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D014157:Transcription Factors; C493754:E2f1 protein, mouse; C032881:lysophosphatidic acid