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Coordinated activation of AMP-activated protein kinase, extracellular signal-regulated kinase, and autophagy regulates phorbol myristate acetate-induced differentiation of SH-SY5Y neuroblastoma cells.
J Neurochem. 2015 Apr; 133(2):223-32.JN

Abstract

We explored the interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK), extracellular signal-regulated kinase (ERK), and autophagy in phorbol myristate acetate (PMA)-induced neuronal differentiation of SH-SY5Y human neuroblastoma cells. PMA-triggered expression of neuronal markers (dopamine transporter, microtubule-associated protein 2, β-tubulin) was associated with an autophagic response, measured by the conversion of microtubule-associated protein light chain 3 (LC3)-I to autophagosome-bound LC3-II, increase in autophagic flux, and expression of autophagy-related (Atg) proteins Atg7 and beclin-1. This coincided with the transient activation of AMPK and sustained activation of ERK. Pharmacological inhibition or RNA interference-mediated silencing of AMPK suppressed PMA-induced expression of neuronal markers, as well as ERK activation and autophagy. A selective pharmacological blockade of ERK prevented PMA-induced neuronal differentiation and autophagy induction without affecting AMPK phosphorylation. Conversely, the inhibition of autophagy downstream of AMPK/ERK, either by pharmacological agents or LC3 knockdown, promoted the expression of neuronal markers, thus indicating a role of autophagy in the suppression of PMA-induced differentiation of SH-SY5Y cells. Therefore, PMA-induced neuronal differentiation of SH-SY5Y cells depends on a complex interplay between AMPK, ERK, and autophagy, in which the stimulatory effects of AMPK/ERK signaling are counteracted by the coinciding autophagic response. Phorbol myristate acetate (PMA) induces the expression of dopamine transporter, microtubule-associated protein 2, and β-tubulin, and subsequent neuronal differentiation of SH-SY5Y neuroblastoma cells through AMP-activated protein kinase (AMPK)-dependent activation of extracellular signal-regulated kinase (ERK). The activation of AMPK/ERK axis also induces the expression of beclin-1 and Atg7, and increases LC3 conversion, thereby triggering the autophagic response that counteracts differentiation process.

Authors+Show Affiliations

Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25348263

Citation

Zogovic, Nevena, et al. "Coordinated Activation of AMP-activated Protein Kinase, Extracellular Signal-regulated Kinase, and Autophagy Regulates Phorbol Myristate Acetate-induced Differentiation of SH-SY5Y Neuroblastoma Cells." Journal of Neurochemistry, vol. 133, no. 2, 2015, pp. 223-32.
Zogovic N, Tovilovic-Kovacevic G, Misirkic-Marjanovic M, et al. Coordinated activation of AMP-activated protein kinase, extracellular signal-regulated kinase, and autophagy regulates phorbol myristate acetate-induced differentiation of SH-SY5Y neuroblastoma cells. J Neurochem. 2015;133(2):223-32.
Zogovic, N., Tovilovic-Kovacevic, G., Misirkic-Marjanovic, M., Vucicevic, L., Janjetovic, K., Harhaji-Trajkovic, L., & Trajkovic, V. (2015). Coordinated activation of AMP-activated protein kinase, extracellular signal-regulated kinase, and autophagy regulates phorbol myristate acetate-induced differentiation of SH-SY5Y neuroblastoma cells. Journal of Neurochemistry, 133(2), 223-32. https://doi.org/10.1111/jnc.12980
Zogovic N, et al. Coordinated Activation of AMP-activated Protein Kinase, Extracellular Signal-regulated Kinase, and Autophagy Regulates Phorbol Myristate Acetate-induced Differentiation of SH-SY5Y Neuroblastoma Cells. J Neurochem. 2015;133(2):223-32. PubMed PMID: 25348263.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Coordinated activation of AMP-activated protein kinase, extracellular signal-regulated kinase, and autophagy regulates phorbol myristate acetate-induced differentiation of SH-SY5Y neuroblastoma cells. AU - Zogovic,Nevena, AU - Tovilovic-Kovacevic,Gordana, AU - Misirkic-Marjanovic,Maja, AU - Vucicevic,Ljubica, AU - Janjetovic,Kristina, AU - Harhaji-Trajkovic,Ljubica, AU - Trajkovic,Vladimir, Y1 - 2014/11/14/ PY - 2014/07/14/received PY - 2014/09/02/revised PY - 2014/10/10/accepted PY - 2014/10/29/entrez PY - 2014/10/29/pubmed PY - 2015/6/13/medline KW - AMP-activated protein kinase KW - autophagy KW - extracellular signal-regulated kinase KW - neuronal differentiation KW - phorbol myristate acetate SP - 223 EP - 32 JF - Journal of neurochemistry JO - J Neurochem VL - 133 IS - 2 N2 - We explored the interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK), extracellular signal-regulated kinase (ERK), and autophagy in phorbol myristate acetate (PMA)-induced neuronal differentiation of SH-SY5Y human neuroblastoma cells. PMA-triggered expression of neuronal markers (dopamine transporter, microtubule-associated protein 2, β-tubulin) was associated with an autophagic response, measured by the conversion of microtubule-associated protein light chain 3 (LC3)-I to autophagosome-bound LC3-II, increase in autophagic flux, and expression of autophagy-related (Atg) proteins Atg7 and beclin-1. This coincided with the transient activation of AMPK and sustained activation of ERK. Pharmacological inhibition or RNA interference-mediated silencing of AMPK suppressed PMA-induced expression of neuronal markers, as well as ERK activation and autophagy. A selective pharmacological blockade of ERK prevented PMA-induced neuronal differentiation and autophagy induction without affecting AMPK phosphorylation. Conversely, the inhibition of autophagy downstream of AMPK/ERK, either by pharmacological agents or LC3 knockdown, promoted the expression of neuronal markers, thus indicating a role of autophagy in the suppression of PMA-induced differentiation of SH-SY5Y cells. Therefore, PMA-induced neuronal differentiation of SH-SY5Y cells depends on a complex interplay between AMPK, ERK, and autophagy, in which the stimulatory effects of AMPK/ERK signaling are counteracted by the coinciding autophagic response. Phorbol myristate acetate (PMA) induces the expression of dopamine transporter, microtubule-associated protein 2, and β-tubulin, and subsequent neuronal differentiation of SH-SY5Y neuroblastoma cells through AMP-activated protein kinase (AMPK)-dependent activation of extracellular signal-regulated kinase (ERK). The activation of AMPK/ERK axis also induces the expression of beclin-1 and Atg7, and increases LC3 conversion, thereby triggering the autophagic response that counteracts differentiation process. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/25348263/Coordinated_activation_of_AMP_activated_protein_kinase_extracellular_signal_regulated_kinase_and_autophagy_regulates_phorbol_myristate_acetate_induced_differentiation_of_SH_SY5Y_neuroblastoma_cells_ L2 - https://doi.org/10.1111/jnc.12980 DB - PRIME DP - Unbound Medicine ER -