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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 E2F1 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.
| Abbreviations | ||
| BD: | = | Butanol‐diethyl ether |
| BSA: | = | Fatty acid‐free bovine serum albumin fraction V |
| CDK: | = | cyclin‐dependent kinase |
| CM: | = | Chloroform‐methanol |
| dlFBS: | = | Delipidated foetal bovine serum |
| FBS: | = | Foetal bovine serum |
| GPCR: | = | G protein‐coupled receptor |
| IL‐2: | = | Interleukin‐2 |
| IL‐3: | = | Interleukin‐3 |
| IL‐2R: | = | Interleukin‐2 receptor |
| IL‐3R: | = | Interleukin‐3 receptor |
| LPA: | = | Lysophosphatidic acid |
| PBS: | = | Phosphate buffered saline |
| PCNA: | = | Proliferating cell nuclear antigen |
| PI3K: | = | Phosphatidylinositol 3‐kinase |
| pRB: | = | Retinoblastoma protein |
| PTK: | = | Protein tyrosine kinase |