Dissociation of cAMP-stimulated Mitogenesis from Activation of the Mitogen-activated Protein Kinase Cascade in Swiss 3T3 Cells

Withers, Dominic J.; Bloom, Stephen R.; Rozengurt, Enrique

doi:10.1074/jbc.270.36.21411

Cited by 56 publications

(48 citation statements)

References 53 publications

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“…However, it has also been reported that PKA-mediated inhibition of cell growth may occur through modulation of intracellular targets distinct from the ERKs cascade (McKenzie and Pouysségur, 1996). On the other hand, PKA is able to stimulate the ERKs cascade in PC12 and in epithelial cells (Frodin et al, 1994;Vossler et al, 1997), and it is also involved in non-ERKsstimulated mitogenic pathways (Withers et al, 1995). Taken together, such findings suggest that cAMP and PKA may produce different and apparently conflicting effects on mitogen-activated signal transduction pathways.…”

mentioning

confidence: 72%

8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor

et al. 1999

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SummaryThe growth factor-activated mitogenic pathways are often disregulated in tumour cells and, therefore, they can provide specific molecular targets for novel anti-tumour approaches. 8-Chloro-cAMP (8-Cl-cAMP), a synthetic cAMP analogue, is a novel anti-tumour agent that has recently undergone clinical evaluation. We investigated the effects of 8-CI-cAMP on the epidermal growth factor (EGF)/EGF receptor (EGF-R) signalling in human epidermoid cancer KB cells, which are responsive to the mitogenic stimulus of EGF. We found that the growthpromoting activity of EGF was completely abolished when EGF treatment was performed in combination with 8-CI-cAMP. The inhibition of the EGF-induced proliferation by 8-CI-cAMP was paralleled by the blockade of the EGF-stimulated activation of mitogen-activated protein kinases (MAPK), ERK-1 and ERK-2. Conversely, we found an increase of EGF-R expression and EGF-R tyrosine phosphorylation when KB cells were growth inhibited by 8-Cl-cAMP. Moreover, the activity of Raf-1 and MEK-1 protein kinases, the activators upstream MAPK in the phosphorylation cascade induced by EGF, was not modified in 8-Cl-cAMP-treated cells. We concluded that the impairment of KB cell response to EGF, induced by 8-Cl-cAMP, resides in the specific inhibition of MAPK/ERKs activity while the function of the upstream elements in the EGF-R signalling is preserved.

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confidence: 72%

8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor

et al. 1999

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“…The inhibition of basal and stimulated p70 S6k activity in hepatocytes by glucagon is consistent with studies in other cell types in which cAMP is antiproliferative, 44,45 although stimulation of p70 S6k by agents increasing intracellular cAMP has been shown in cells in which cAMP is mitogenic. 46,47 The inhibition of interleukin-2-stimulated p70 S6k activity in T lymphocytes and smooth muscle cells by cAMP occurs at the level of PI 3-kinase. 44,45 TGF-␤ has no effect on either basal or stimulated levels of cAMP in hepatocytes, 6 and, on the basis of our results, no effect on the activity of PKB or, by inference, PI 3 kinase.…”

Section: Fig 3 Tgf-␤ and Glucagon Do Not Inhibit Egf-induced Jnk1 Omentioning

confidence: 99%

Inhibition of rat hepatocyte proliferation by transforming growth factor ? and glucagon is associated with inhibition of ERK2 and p70 S6 kinase

Dixon¹,

Agius²,

Yeaman

et al. 1999

Hepatology

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Stimulation of hepatocyte proliferation by epidermal growth factor (EGF) and insulin is inhibited by transforming growth factor ␤ (TGF-␤) and by glucagon. It is also suppressed by inhibitors of various protein kinases, including rapamycin, which blocks activation of p70 S6 kinase (p70 S6k ), PD98059, which inhibits the activation of extracellular-regulated kinase (ERK), and SB 203580, an inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK). In this study, we investigated whether the inhibition of proliferation by TGF-␤ involves these protein kinase cascades. Culture of hepatocytes with TGF-␤ for 16 hours decreased the stimulation by EGF of ERK2 and p70 S6k (by 50% and 35%, respectively), but did not affect the stimulation of either p38 MAPK, c-jun NH 2 -terminal kinase (JNK), or protein kinase B (PKB). Culture of hepatocytes with glucagon for 16 hours also inhibited the stimulation by EGF of activation of ERK2 and p70 S6k (by E50%). The inhibitory effects of glucagon were observed when the hormone was added either 10 minutes or 60 minutes before EGF addition, whereas no effects of TGF-␤ were observed after 10-minute or 60-minute incubation. These results suggest that the inhibition of hepatocyte proliferation by TGF-␤ may be in part mediated by inhibition of ERK2 and p70 S6k , but does not involve PKB, JNK, or p38 MAPK. Unlike glucagon, the effects of TGF-␤ are not elicited in response to short-term treatment. (HEPATOLOGY 1999;29:1418-1424 Hepatocyte proliferation following injury or partial hepatectomy is regulated by the action of both stimulatory (mitogenic) and inhibitory growth factors and hormones (reviewed in Michalopoulos 1 and Fausto 2 ). Studies in primary hepatocyte cultures have identified several complete mitogens capable of inducing DNA synthesis in serum-free medium,

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“…Stimulation of quiescent cultures of these cells by either phorbol ester-mediated protein kinase C (PKC) activation, cAMP-mediated protein kinase A (PKA) activation or by insulin is not sucient to promote reinitiation of DNA synthesis. However, any combination of these signals can induce quiescent Swiss 3T3 cells to exit G 0 and re-enter the cell cycle (Albert and Rozengurt, 1992;Withers et al, 1995;Seuerlein et al, 1996). The neuropeptide bombesin, which activates multiple second messenger pathways in these cells (Rozengurt, 1995), can induce a proliferative response in the absence of any other exogenously added signal but its mitogenic eect is markedly potentiated by the addition of insulin (Rozengurt and Sinnett-Smith, 1983).…”

Section: Introductionmentioning

confidence: 99%

Differential control of cyclins D1 and D3 and the cdk inhibitor p27Kip1 by diverse signalling pathways in Swiss 3T3 cells

et al. 1997

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Dissociation of cAMP-stimulated Mitogenesis from Activation of the Mitogen-activated Protein Kinase Cascade in Swiss 3T3 Cells

Cited by 56 publications

References 53 publications

8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor

8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor

Inhibition of rat hepatocyte proliferation by transforming growth factor ? and glucagon is associated with inhibition of ERK2 and p70 S6 kinase

Differential control of cyclins D1 and D3 and the cdk inhibitor p27Kip1 by diverse signalling pathways in Swiss 3T3 cells

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