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TNF Down-Regulation of Receptor Tyrosine Kinase

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TNF Down-Regulation of Receptor Tyrosine Kinase Cell Death and Differentiation (2000) 7, 955 ± 965 ã 2000 Macmillan Publishers Ltd All rights reserved 1350-9047/00 $15.00 www.nature.com/cdd TNF down-regulation of receptor tyrosine kinase- dependent mitogenic signal pathways as an important step in cytostasis induction and commitment to apoptosis of Kym-1 rhabdomyosarcoma cells Peter Storz1, Heike DoÈ ppler1, Judith Horn-MuÈ ller1, Introduction 1 ,1 Gertraud MuÈ ller and Klaus P®zenmaier* Tumor necrosis factor (TNF) is an important mediator of inflammation and inducer of cell death in a variety of cell types 1 Institute of Cell Biology and Immunology, University of Stuttgart, Germany via TNF-R1 and TNF-R2-dependent engagement of multiple * Corresponding author: K P®zenmaier, Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, D-70569 Stuttgart, signal pathways, typically resulting in NF-kBandJNK Germany. Tel: 49 711 685 6986; Fax: 49 711 685 7484; activation in virtually all cells, as well as induction of caspase 1,2 E-mail: klaus.p®[email protected] cascades in cells sensitive to apoptosis (for reviews see ). Due to the potentially simultaneous activation of pro- and Received 25.1.00; revised 9.6.00; accepted 19.6.00 antiapoptotic signal pathways by TNF, the cellular context, i.e. Edited by D Wallach the qualitative and quantitative constitution with the respective signal components, determines the cellular fate in response to TNF. In addition to the direct activation of proinflammatory and Abstract apoptotic signal cascades, it becomes increasingly evident Growth of Kym-1 rhabdomyosarcoma cells depends on that TNF signals also affect other signal cascades and, in endogenous receptor tyrosine kinase signals activated by particular, interfere with several receptor tyrosine kinase- insulin and insulin-like growth factors (IGF), as revealed from mediated activities. For example, the TNF crosstalk with enhancement of proliferation by insulin and IGF-1 and insulin signal pathways has received much attention in recent years, because a link and potential causal relationship to the cytostatic action of inhibitors of IR/IGFR kinases. Depending development of insulin resistance, a widespread pathophy- on the presence or absence of the caspase inhibitor z-VAD- siological condition leading to NIDDM, has been proposed.3 fmk, TNF induced full growth arrest or apoptosis, respectively, This is based on both in vitro cell models with adipocytes and indicating dominance of TNF over mitogenic signal pathways hepatocytes, where TNF interfered with insulin-induced IR in Kym-1 cells. In accordance with a caspase-independent activation,4,5 as well as in vivo models of genetic or dietary cytostatic action, TNF downregulated IR kinase activity and development of obesity and diabetes, showing amelioration of caused a profound inhibition of downstream mitogenic insulin resistance in TNF- or TNFR-k/o mice.6 The signals including the MAPK cascade and STAT5, key responsible molecular mechanisms of this TNF crosstalk pathways of proliferation and cell survival. Removal of z- are not yet understood and may operate at various levels of VAD-fmk after 24 h induced rapid cell death in the absence of the insulin signal cascade, probably involving a down- 7 TNF. The inhibition of survival signals concomitant with regulation of the glucose transporter GLUT4 itself, inhibition of IRS-1 function,5,8,9 and direct inhibition of IRb kinase persisting proapoptotic signals may tip the balance towards activity.10 ± 12 However, the partial inhibition of IRb kinase an irreversible commitment of the cell to apoptosis that activity appears by itself not sufficient to explain reduced becomes apparent upon relief of suppression of effector glucose uptake, as in muscle cells the latter is not affected by caspases. Cell Death and Differentiation (2000) 7, 955 ± 965. TNF despite a down-regulation of IRb kinase and immediate downstream substrates.13 In addition to the prominent IR Keywords: TNF signal crosstalk; MAPK pathway; STAT5; growth signal tranducer IRS-1, STAT5b was recently recognized as a arrest; apoptosis direct substrate.12,14,15 Both, IRS-1 and STAT5b are considered as important regulators of proliferative and Abbreviations: EMSA, electrophoretic mobility shift assay; antiapoptotic responses.16 ± 22 IRS-1 proteins act as inter- GLUT4, glucose transporter 4; IRb, insulin receptor b chain; IGFR, faces between stimulated receptors and downstream signal- insulin-like growth factor receptor; IRS-1, insulin receptor substrate ing proteins with SH2 (src homology 2) domains such as Grb2 1; JNK, c-Jun-N-terminal kinase; MAPK, mitogen-activated protein and Shc, which activate the MAP kinase (MAPK) kinase; NF-kB, nuclear factor-kB; NIDDM, non-insulin-dependent cascade23 ± 25 and PI 3-kinase (phosphatidylinositol-3-OH diabetes mellitus, PIP3, phosphatidylinositol-3,4,5-trisphosphate; kinase), whose product PIP3 (phosphatidylinisitol-3,4,5-tri- TNF/R, tumor necrosis factor/receptors; RTK, receptor tyrosine sphosphate) is an activator of Akt/PKB (protein kinase B). kinases;STAT5,signaltransducerandactivatoroftranscription5;z- Interestingly, not only Akt/PKB, which function to promote cell VAD-fmk, z-Val-Ala-DL-Asp-¯uoromethylketone survival by inhibiting apoptosis at various levels,26,27 but also STAT5 are constitutively active in an apoptosis-resistant cell line,22 suggesting that besides Akt/PKB, STAT5 and STAT5 TNF crosstalk with mitogenic RTK signal pathways PStorzet al 956 dependent genes also might play a role in the prevention of Both inhibitors caused a dose-dependent inhibition of apoptosis. Accordingly, TNF mediated crosstalk with insulin proliferation (Figure 1D, E), but not induction of apoptosis signaling could extend beyond an interference with insulin's (as revealed from microscopical examination as well as immediate metabolic effects causing insulin resistance and propidium iodide staining, data not shown) within the affect signal pathways regulating the transcriptional program observation period. In fact, at the highest dose employed, a and cellular functions related to growth control and survival. complete growth arrest was achieved as evident from the To further substantiate at a molecular level the extent of MTT signal obtained from an aliquot of freshly seeded cells the TNF crosstalk with mitogenic RTK-mediated signals stained directly after attachment to culture dishes (Figure 1D, induced by insulin and to analyze the functional con- E), asterisk and dotted line). Together, these data suggest an sequences with respect to growth control and apoptosis essential participation of IR/IGFR induced signals to the sensitivity, we have studied a human rhabdomyosarcoma proliferative capacity of Kym-1 cells. cell line, Kym-1. Although these cells display an endogen- ous activation of the related insulin-like growth factor receptor (IGFR), which shares the activation of several TNF down-regulates insulin-induced activation of intracellular signal pathways, in particular IRS-1 activation, mitogenic signal pathways in Kym-1 cells with the IR,28 Kym-1 cells are responsive to exogenous Recently, a negative regulatory crosstalk between insulin and insulin treatment with respect to IRS-1 activation.15 As TNF signaling cascades has been identified, a hallmark being Kym-1 cells are also highly sensitive to TNF and rapidly the inhibition of insulin-induced, GLUT4-mediated glucose undergo apoptosis,29,30 the insulin signal pathways poten- uptake in adipocytes,4 whereas in muscle cells, this crosstalk tially affected by TNF were investigated under conditions of does apparently not affect glucose transport.13 Kym-1 cells blocking the apoptotic effector phase by caspase inhibitors. are TNF-responsive as evident from rapid, but transient NF- The data obtained show an early inhibition of insulin- kB activation (Figure 2A), and the later induction of apoptosis induced mitogenic and potentially antiapoptotic signals, without conditioning of the cells by protein synthesis resulting in a complete growth arrest during a two day inhibitors29,30 (Figure4A).Inaccordancewithprevious culture. In parallel, within 24 h, cells become irreversibly results obtained in other cell models4,5,11,12 a2hTNF committed to death; upon removal of the broad spectrum pretreatment of Kym-1 cells resulted in a typical amelioration caspase inhibitor z-VAD-fmk, cells undergo apoptosis in the of the subsequent insulin response, with a partial (30 ± 50%) absence of exogenous TNF. The rapid, profound and reduction of IRb kinase activity (Figure 2B). In these cells, lasting inhibition of mitogenic/antiapoptotic signals could be significant TNF mediated caspase activation can only be an essential step towards progression to apoptosis. revealed after approximately 3 h of TNF treatment.30 Never- theless, to ensure that low levels of active caspases did not influence early events in the signal crosstalk between TNF Results and insulin, z-VAD-fmk, an effective, broad spectrum inhibitor of caspases,34 was added throughout the TNF pretreatment Kym-1 rhabdomyosarcoma growth depends on and subsequent stimulation period. Immunoblot analyses functional insulin/IGF signal pathways verified down-regulation of IRb kinase activity by TNF also in The functionality of the IR signaling was first verified by the presence of z-VAD-fmk (Figure 2C), indicating caspase Western blot analyses of tyrosine phosphorylation of independence of this inhibitory crosstalk. As a consequence immunoprecipitated IRb and IRS-1. Upon insulin treatment of reduced
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