Separate Cyclic AMP Sensors for Neuritogenesis, Growth Arrest, and Survival of Neuroendocrine Cells

Emery, Andrew C.; Eiden, Maribeth V.; Eiden, Lee E.

doi:10.1074/jbc.m113.529321

“…This result is not surprising, since these genes contain TRE sequences in their regulatory regions (57)(58)(59). The high levels of D1 expression induced by T3 are consistent with the positive feedback loop of the processes for NE differentiation (47). PKA directly induces the inactivation of an apoptotic factor (phosphorylation of BAD) (9), and it indirectly stimulates VEGF secretion (PI3K/AKT/hypoxia inducible factor-1α [HIF-1α]) (48) and neurite outgrowth by cytoskeleton rearrangements (inhibition of Ras homolog gene family A [RhoA]/Rho-associated protein kinase [ROCK]) (49).…”

Section: Discussionsupporting

confidence: 57%

“…Along this line, our data confirm an association between acquisition of the NE phenotype and high levels of pCREB in ISO-treated LNCaP cells. We did not analyze EPAC/p38-MAP kinase activation, but it is known that this intermediate effector is related to cell arrest in pheochromocytoma cells (47).…”

Section: Discussionmentioning

confidence: 99%

Triiodothyronine Attenuates Prostate Cancer Progression Mediated by β-Adrenergic Stimulation

Delgado‐González

¹

,

Sánchez-Tusié

²

,

Morales

³

et al. 2016

Mol Med

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Prostate cancer cells are responsive to adrenergic and thyroid stimuli. It is well established that β-adrenergic activation (protein kinase A [PKA]/cAMP response element binding protein [CREB]) promotes cancer progression, but the role of thyroid hormones is poorly understood. We analyzed the effects of β-adrenergic stimulation (isoproterenol [ISO]) and/or thyroid hormone on neuroendocrine (NE) differentiation and cell invasion, using in vivo (LNCaP tumor) and in vitro models (LNCaP and DU145 human cells). Nude mice were inoculated with LNCaP cells and were treated for 6 wks with ISO (200 μg/d), triiodothyronine (T3, 2.5 μg/d) or both. ISO alone reduced tumor growth but increased tumor expression of cAMP response element (CRE)-dependent genes (real-time polymerase chain reaction, chromogranin A, neuron-specific enolase, survivin, vascular endothelial growth factor [VEGF], urokinase plasmin activator [uPA] and metalloproteinase-9 [MMP-9]) and some proteins related to NE differentiation and/or invasiveness (synaptophysin, VEGF, pCREB). T3 reduced tumor growth and prevented the overexpression of ISO-stimulated factors through a pCREB-independent mechanism. In low invasive LNCaP cells, 50 μmol/L ISO or 100 nmol/L thyroxine (T4) induced the acquisition of NE-like morphology (phase-contrast microscopy), increased VEGF secretion (ELISA) and invasive capacity (Transwell assay), but no synergistic effects were observed after the coadministration of ISO + T4. In contrast, 10 nmol/L T3 alone had no effect, but it prevented the NE-like morphology and invasiveness stimulated by ISO. None of these treatments had any effect on highly invasive DU145 cells. In summary, this study showed that ISO and T4 increase cancer progression, and T3 attenuates ISO-stimulated progression. Further studies are required to determine if changes in the ratio of T4/T3 could be relevant for prostate cancer progression.

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“…Cell biological outcomes of crosstalk from cAMP to ERK1/2 have been extensively studied in the rat pheochromocytoma cell line PC12 (Emery et al, 2014(Emery et al, , 2013Vaillancourt et al, 1994). PC12 cells differentiate to a neuroendocrine phenotype upon stimulation with GPCR ligands or growth factors.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk from cAMP to ERK1/2 emerges during postnatal maturation of nociceptive neurons and is maintained during aging

Isensee

¹

,

Schild

²

,

Schwede

³

et al. 2017

Journal of Cell Science

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Maturation of nociceptive neurons depends on changes in transcription factors, ion channels and neuropeptides. Mature nociceptors initiate pain in part by drastically reducing the activation threshold via intracellular sensitization signaling. Whether sensitization signaling also changes during development and aging remains so far unknown. Using a novel automated microscopy approach, we quantified changes in intracellular signaling protein expression and in their signaling dynamics, as well as changes in intracellular signaling cascade wiring, in sensory neurons from newborn to senescent (24 months of age) rats. We found that nociceptive subgroups defined by the signaling components protein kinase A (PKA)-RIIβ (also known as PRKAR2B) and CaMKIIα (also known as CAMK2A) developed at around postnatal day 10, the time of nociceptor maturation. The integrative nociceptor marker, PKA-RIIβ, allowed subgroup segregation earlier than could be achieved by assessing the classical markers TRPV1 and Na v 1.8 (also known as SCN10A). Signaling kinetics remained constant over lifetime despite in part strong changes in the expression levels. Strikingly, we found a mechanism important for neuronal memory -i.e. the crosstalk from cAMP and PKA to ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1, respectively) -to emerge postnatally. Thus, maturation of nociceptors is closely accompanied by altered expression, activation and connectivity of signaling pathways known to be central for pain sensitization and neuronal memory formation.

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“…PC12 cells differentiate to a neuroendocrine phenotype upon stimulation with GPCR ligands or growth factors. There, recent research demonstrates that neuritogenesis requires RapGEF2-dependent activation of ERK1/2, whereas Epac2 (also known as RapGEF4) activates the p38 MAPK family to mediate growth arrest, and PKA is involved in cAMP-dependent protection from serum withdrawalinduced cell death (Emery et al, 2014). It will be of interest to investigate in depth which of the cAMP-dependent intracellular signaling components mediates the crosstalk to ERK1/2 and which cellular functions are thereby modulated.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk from cAMP to ERK1/2 emerges during postnatal maturation of nociceptive neurons and is maintained during aging

Isensee¹,

Schild²,

Schwede³

et al. 2017

View full text Add to dashboard Cite

Maturation of nociceptive neurons depends on changes in transcription factors, ion channels and neuropeptides. Mature nociceptors initiate pain in part by drastically reducing the activation threshold via intracellular sensitization signaling. Whether sensitization signaling also changes during development and aging remains so far unknown. Using a novel automated microscopy approach, we quantified changes in intracellular signaling protein expression and in their signaling dynamics, as well as changes in intracellular signaling cascade wiring, in sensory neurons from newborn to senescent (24 months of age) rats. We found that nociceptive subgroups defined by the signaling components protein kinase A (PKA)-RIIβ (also known as PRKAR2B) and CaMKIIα (also known as CAMK2A) developed at around postnatal day 10, the time of nociceptor maturation. The integrative nociceptor marker, PKA-RIIβ, allowed subgroup segregation earlier than could be achieved by assessing the classical markers TRPV1 and Na v 1.8 (also known as SCN10A). Signaling kinetics remained constant over lifetime despite in part strong changes in the expression levels. Strikingly, we found a mechanism important for neuronal memory -i.e. the crosstalk from cAMP and PKA to ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1, respectively) -to emerge postnatally. Thus, maturation of nociceptors is closely accompanied by altered expression, activation and connectivity of signaling pathways known to be central for pain sensitization and neuronal memory formation.

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Separate Cyclic AMP Sensors for Neuritogenesis, Growth Arrest, and Survival of Neuroendocrine Cells

Cited by 36 publications

References 58 publications

Triiodothyronine Attenuates Prostate Cancer Progression Mediated by β-Adrenergic Stimulation

Triiodothyronine Attenuates Prostate Cancer Progression Mediated by β-Adrenergic Stimulation

Crosstalk from cAMP to ERK1/2 emerges during postnatal maturation of nociceptive neurons and is maintained during aging

Crosstalk from cAMP to ERK1/2 emerges during postnatal maturation of nociceptive neurons and is maintained during aging

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