Phosphatidylinositol 3-Kinase Couples the Interleukin-2 Receptor to the Cell Cycle Regulator E2F

Brennan, Paul; Babbage, Jane W; Burgering, Boudewijn M.T.; Groner, Bernd; Reif, Karin; Cantrell, Doreen A.

doi:10.1016/s1074-7613(00)80388-x

Cited by 373 publications

(345 citation statements)

References 61 publications

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“…The downstream e ectors of the PI 3-kinase involved in the G1-S progression in Ba/F3 cells are not known. One candidate could be the cell cycle regulator E2F which has been shown to be a target of PI 3-kinase in T-cells (Brennan et al, 1997). Expression of proteins involved in G1-S transition like cyclins D, cyclin dependent kinases and inhibitors of cycline dependent kinases will require also careful analysis.…”

Section: Discussionmentioning

confidence: 99%

Cooperation between STAT5 and phosphatidylinositol 3-kinase in the IL-3-dependent survival of a bone marrow derived cell line

et al. 2000

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Cytokine-dependent activation of distinct signaling pathways is a common scheme thought to be required for the subsequent programmation into cell proliferation and survival. The PI 3-kinase/Akt, Ras/MAP kinase, Ras/ NFIL3 and JAK/STAT pathways have been shown to participate in cytokine mediated suppression of apoptosis in various cell types. However the relative importance of these signaling pathways seems to depend on the cellular context. In several cases, individual inhibition of each pathway is not su cient to completely abrogate cytokine mediated cell survival suggesting that cooperation between these pathways is required. Here we showed that individual inhibition of STAT5, PI 3-kinase or MEK activities did not or weakly a ected the IL-3 dependent survival of the bone marrow derived Ba/F3 cell line. However, the simultaneous inhibition of STAT5 and PI 3-kinase activities but not that of STAT5 and MEK reduced the IL-3 dependent survival of Ba/F3. Analysis of the expression of the Bcl-2 members indicated that phosphorylation of Bad and Bcl-x expression which are respectively regulated by the PI 3-kinase/Akt pathway and STAT5 probably explain this cooperation. Furthermore, we showed by co-immunoprecipitation studies and pull down experiments with fusion proteins encoding the GST-SH2 domains of p85 that STAT5 in its phosphorylated form interacts with the p85 subunit of the PI 3-kinase. These results indicate that the activations of STAT5 and the PI 3-kinase by IL-3 in Ba/F3 cells are tightly connected and cooperate to mediate IL-3-dependent suppression of apoptosis by modulating Bad phosphorylation and Bcl-x expression.

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Section: Discussionmentioning

confidence: 99%

Cooperation between STAT5 and phosphatidylinositol 3-kinase in the IL-3-dependent survival of a bone marrow derived cell line

et al. 2000

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“…Therefore, the proliferative advantage of HTLV-I-transformed Tcells may be related to the maintenance of limiting amount of p27 Kip1 , as also suggested by the ®nding that the amount of p27 Kip1 is lower in transformed than immortalized T-cells. It has been shown that IL-2 decreases the stability of p27 Kip1 by increasing its proteolysis (Pagano et al, 1995); this event is presumably mediated by PI3K phosphorylation activity (Brennan et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…A recent report suggests that the regulation of p27 Kip1 expression by IL-2 occurs through the activity of P13K (Brennan et al, 1997). To investigate whether the decreased amount of p27 Kip1 observed in HTLV-Itransformed T-cells results from the constitutive activation of P13K, three IL-2-dependent and four IL-2-independent HTLV-I-infected T-cell lines and PHA-PBMC were treated with the speci®c inhibitor of P13K, LY294002, and analysed 24 h later for p27 Kip1 expression and DNA content.…”

Section: P13k Inhibition Is Associated With Upregulation Of P27 Kip1 mentioning

confidence: 99%

Limiting amounts of p27Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells

et al. 1999

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“…To further con®rm the involvement of these pathways, we carried out Elk-1 transactivation studies with dominant negative constructs of Raf-1 and the p85 subunit of PI3 kinase (Bruder et al, 1992;Brennan et al, 1997). These constructs did not only abrogate the DHT e ect but they also reduced the basal activity which possibly arose as a result of residual hormone in the culture medium (Figure 5a).…”

Section: Sensitivity To Kinase Inhibitorsmentioning

confidence: 99%

Rapid signalling by androgen receptor in prostate cancer cells

Peterziel¹,

Mink²,

Schonert³

et al. 1999

Oncogene

234

157

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Androgens are important growth regulators in prostate cancer. Their known mode of action in target cells requires binding to a cytoplasmic androgen receptor followed by a nuclear translocation event and modulation of the expression of speci®c genes. Here, we report another mode of action of this receptor. Treatment of androgen responsive prostate cancer cells with dihydrotestosterone leads to a rapid and reversible activation of mitogen-activated protein kinases MAPKs (also called extracellular signal-regulated kinases or Erks). Transient transfection assays demonstrated that the androgen receptor-mediated activation of MAP kinase results in enhanced activity of the transcription factor Elk-1. This action of the androgen receptor di ers from its known transcriptional activity since it is rapid and insensitive to androgen antagonists such as hydroxy¯utamide or casodex. Biochemical studies as well as analyses with dominant negative mutants showed the involvement of kinases such as MAPK/Erk kinase, phosphatidyl-inositol 3-kinase and protein kinase C in the androgen receptormediated activation of MAP kinase. These results demonstrate a novel regulatory action of the androgen receptor and prove that in addition to its known transcriptional e ects, it also uses non-conventional means to modulate several cellular signalling processes.

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Phosphatidylinositol 3-Kinase Couples the Interleukin-2 Receptor to the Cell Cycle Regulator E2F

Cited by 373 publications

References 61 publications

Cooperation between STAT5 and phosphatidylinositol 3-kinase in the IL-3-dependent survival of a bone marrow derived cell line

Cooperation between STAT5 and phosphatidylinositol 3-kinase in the IL-3-dependent survival of a bone marrow derived cell line

Limiting amounts of p27Kip1 correlates with constitutive activation of cyclin E-CDK2 complex in HTLV-I-transformed T-cells

Rapid signalling by androgen receptor in prostate cancer cells

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