Differentiation of PC12 cells in response to a cAMP analogue is accompanied by sustained activation of mitogen‐activated protein kinase

Young, Stephen W.; Dickens, Martin; Tavaré, Jeremy M.

doi:10.1016/0014-5793(94)80367-6

Cited by 127 publications

(96 citation statements)

References 29 publications

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“…The activation of MAP kinase by cAMP has been suggested to be involved in the neuronal differentiation of PC12 cells (3,16,51,52) and the melanogenesis in melanoma cells (46). In light of these observations it is interesting that PYS-2 cells resemble parietal endoderm cells (40).…”

Section: Discussionmentioning

confidence: 99%

Parathyroid Hormone Activates Mitogen-activated Protein Kinase via a cAMP-mediated Pathway Independent of Ras

Verheijen

Defize

1997

Journal of Biological Chemistry

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In a previous study, we demonstrated that parathyroid hormone (PTH) inhibits mitogen-activated protein (MAP) kinase activation in osteosarcoma cells via a protein kinase A-dependent pathway. Here, we show that PTH can induce a transient activation of MAP kinase as well. This was observed in both Chinese hamster ovary R15 cells stably expressing high levels of rat PTH/PTHrelated peptide receptor and parietal yolk sac carcinoma cells expressing the receptor endogenously. PTH was a strong activator of adenylate cyclase and phospholipase C in Chinese hamster ovary R15 cells. PTHinduced MAP kinase activation did not depend on activation of G i , phorbol ester-sensitive protein kinase C, elevated intracellular calcium levels, or release of G␤␥ subunits. It could, however, be mimicked by addition of forskolin or 8-bromo-cAMP to these cells. Prolonged treatment with forskolin caused sustained protein kinase A activity, whereas MAP kinase activity returned to basal levels. Subsequent treatment with PTH or 8-bromo-cAMP did not result in MAP kinase activation, whereas phorbol ester-or insulin-induced MAP kinase activation was unaffected. Finally, expression of a dominant negative form of Ras (Ras Asn-17 ), which completely blocked insulin-induced MAP kinase activation, did not affect activation by PTH or cAMP. In conclusion, PTH regulates MAP kinase activity in a cell type-specific fashion. The activation of MAP kinase by PTH is mediated by cAMP and independent of Ras.Mitogen activated protein (MAP) 1 kinases are protein serine and threonine kinases that play an important role in the regulation of cell growth and differentiation (1-3). The activity of MAP kinase is under the control of external stimuli that mediate their effects by binding to cell surface receptors. Protein tyrosine kinase receptors transduce the signal by autophosphorylation of tyrosine residues, allowing the receptor to interact with Src homology 2 domain-containing proteins, such as Grb2, which will recruit son of sevenless, resulting in the activation of Ras. This will cause the successive activation of Raf-1, MAP kinase kinase (MEK), and MAP kinase (4).G protein-coupled receptors (GPCRs) regulate MAP kinase activity, depending on the identity of the G protein, the receptor, and the cell type involved. G i -coupled receptors, such as the M2 muscarine acetylcholine receptor, the ␣ 2 -adrenergic receptor, or the receptors for lysophosphatidic acid (LPA) or thrombin, stimulate MAP kinase in a Ras-dependent manner (5-7). Recent reports have shown that MAP kinase activation through G i involves the release of G␤␥ subunits (8 -11), which via an as yet unidentified tyrosine kinase induce the phosphorylation of Shc, leading to the formation of a Shc-Grb2-son of sevenless complex (12, 13) and activation of Ras.For receptors coupled to G q , such as the M1 acetylcholine receptor, the ␣ 1 -adrenergic receptor, or the bombesin receptor, both ␤␥ subunit-dependent (10) and ␤␥ subunit-independent (8, 11) activation of MAP kinase has been reported. The ␤␥ subunit-indu...

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Section: Discussionmentioning

confidence: 99%

Parathyroid Hormone Activates Mitogen-activated Protein Kinase via a cAMP-mediated Pathway Independent of Ras

Verheijen

Defize

1997

Journal of Biological Chemistry

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“…Indeed, the role of signalling by the MAP kinase cascade in terms of either cellular proliferation or cellular differentiation is currently under intensive study and recent reports using other cell types have suggested a role for chronic MAP kinase activation in causing exit from the cell cycle followed by cellular differentiation [11][12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic

Tombes

Auer

Mikkelsen

et al. 1998

Biochemical Journal

179

155

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Bailie et al. [In Vitro Cell Dev. Biol. (1992) 28A, 621-624] reported that primary cultures of rat hepatocytes possess low affinity binding sites for nerve growth factor (NGF). NGF treatment of primary cultures of rat hepatocytes with a maximally effective concentration of NGF (20 ng/ml, 0.8 nM) caused acute phasic activation of Raf-1 and p42MAPkinase, and a smaller sustained activation of B-Raf. The transient increase in Raf-1 and p42MAPkinase activity returned to baseline within ~ 30 min. NGF treatment of hepatocytes did not induce expression of cyclin dependent kinase (cdk) inhibitor proteins, but instead stimulated cdk2 activity and increased [3H]thymidine incorporation into DNA. In contrast to hepatocytes, NGF treatment of PC12 pheochromocytoma cells caused large sustained activations of B-Raf and p42MAPkinase, and a lower phasic activation of Raf-1. The sustained activations of B-Raf and p42MAPkinase were for more than 5 h. Treatment of PC12 cells with NGF increased p21Cip1/WAF-1 expression, reduced cdk2 activity and inhibited DNA synthesis, the opposite to the effects of NGF treatment of hepatocytes. However when p42MAPkinase was chronically activated in hepatocytes, via infection with an inducible oestrogen receptor-Raf-1 fusion protein, expression of p21Cip-1/WAF1 and p16INK4a cdk inhibitor proteins increased, cdk2 activity decreased, and DNA synthesis decreased. Equally, treatment of hepatocytes with 50 mM ethanol elevated the basal activity of p42MAPkinase and temporally extended the ability of NGF treatment to activate p42MAPkinase. Ethanol and NGF co-treatment increased expression of p21Cip-1/WAF1 and p16INK4a cdk inhibitor proteins and decreased hepatocyte DNA synthesis. These data demonstrate that NGF can cause either acute/phasic or sustained activation of the MAP kinase cascade in different cell types. Acute activation of the MAP kinase cascade correlated with increased DNA synthesis. In contrast, sustained activation of the MAP kinase cascade correlated with increased expression of cdk inhibitor proteins, a reduction in cdk activity, and an inhibition of DNA synthesis. These data suggest a general mechanism exists where acute activation of the MAP kinase cascade promotes G1 progression/S phase entry and that chronic activation of the MAP kinase cascade inhibits this process.

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“…1). Although the PAC1 receptor couples to both G q and G s G proteins, PACAP-mediated neuritogenesis in PC12 cells is believed to proceed through cAMP because cAMP analogs or cAMP elevation with forskolin mimic the effects of PACAP (16,(20)(21)(22). In addition, neuritogenesis induced by PACAP is blocked by the cAMP antagonist dideoxyadenosine (22), and there is currently no evidence that direct activation of G q -mediated signaling mediates differentiation in PC12 cells.…”

mentioning

confidence: 99%

“…The critical link missing from these studies is the component responsible for cAMPdependent PKA-independent activation of ERK in PC12 cells (3,13,16,20 (24) (Fig. 2).…”

mentioning

confidence: 99%

Regulation of PC12 Cell Differentiation by cAMP Signaling to ERK Independent of PKA: Do All the Connections Add Up?

Gerdin

Eiden

2007

Sci. STKE

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Pituitary adenylate cyclase–activating polypeptide (PACAP) is a neuropeptide that elevates adenosine 3′,5′-monophosphate (cyclic AMP, also abbreviated cAMP) to elicit neuritogenesis in PC12 cells. This effect appears to be independent of cAMP-dependent protein kinase (PKA) yet dependent on cAMP, leading to the conclusion that another cAMP-binding protein and subsequent signaling pathway must exist to mediate this PKA-independent signaling mechanism. Such a protein was identified as exchange protein directly activated by cAMP (EPAC). Although EPAC may play an indirect role in PACAP-mediated neuritogenesis, it does not serve as the only PKA-independent link from cAMP that leads to neuritogenesis. Thus, the challenge remains to construct a signaling network that incorporates the known mediators, working independently of PKA, that are ultimately responsible for PACAP-mediated neuritogenesis.

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Differentiation of PC12 cells in response to a cAMP analogue is accompanied by sustained activation of mitogen‐activated protein kinase

Cited by 127 publications

References 29 publications

Parathyroid Hormone Activates Mitogen-activated Protein Kinase via a cAMP-mediated Pathway Independent of Ras

Parathyroid Hormone Activates Mitogen-activated Protein Kinase via a cAMP-mediated Pathway Independent of Ras

The mitogen-activated protein (MAP) kinase cascade can either stimulate or inhibit DNA synthesis in primary cultures of rat hepatocytes depending upon whether its activation is acute/phasic or chronic

Regulation of PC12 Cell Differentiation by cAMP Signaling to ERK Independent of PKA: Do All the Connections Add Up?

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