Sphingomyelin Synthase 1 Regulates Neuro-2a Cell Proliferation and Cell Cycle Progression Through Modulation of P27 Expression and Akt Signaling

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2014 Aug 3

PMID 25084761

Citations 13

Authors

Umadevi V Wesley

James F Hatcher

Robert J Dempsey

Affiliations

Soon will be listed here.

Abstract

Sphingomyelin synthase (SMS) is a key enzyme involved in the generation of sphingomyelin (SM) and regulation of cell growth and survival. However, the effects of SMS on neuronal cell proliferation and cell cycle progression are not completely elucidated. In this study, we examined the direct effects of SMS1 in regulating cell cycle progression and proliferation of Neuro-2a cells that exhibit neuronal characteristics. Neuro-2a cells transfected with SMS-specific small hairpin RNA (shRNA) expressed significantly lower levels of SMS1. RNA interference-mediated depletion of SMS1 in Neuro-2a cells caused a significant decrease in SM levels. Decreased SMS1 levels resulted in reduced proliferation rate and morphological changes including neurite-like outgrowth. Also, silencing of SMS1 induced cell cycle arrest as shown by the increased percentage of cells in G0/G1 and decreased proportion of cells in S phase. These changes were accompanied by upregulation of cyclin-dependent kinase inhibitor p27 and decreased levels of cyclin D1 and phospho-Akt. Nuclear accumulation of p27 was also evident in SMS1-deficient cells. Furthermore, loss of SMS1 inhibited the migratory potential of Neuro-2a cells in association with decreased levels of matrix metalloproteinases. These results indicate that SMS1 plays an important role in mediating the key signaling pathways that are involved in the tight coordination of multiple cellular activities, including neuronal cell proliferation, cell cycle progression, and migration, and therefore may have significant implications in neurodegenerative diseases.

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References

Adibhatla R, Hatcher J . Protection by D609 through cell-cycle regulation after stroke. Mol Neurobiol. 2010; 41(2-3):206-17. DOI: 10.1007/s12035-010-8100-1. View

Kelly-Spratt K, Philipp-Staheli J, Gurley K, Hoon-Kim K, Knoblaugh S, Kemp C . Inhibition of PI-3K restores nuclear p27Kip1 expression in a mouse model of Kras-driven lung cancer. Oncogene. 2009; 28(41):3652-62. PMC: 2842079. DOI: 10.1038/onc.2009.226. View

Matsuo T, Seth P, Thiele C . Increased expression of p27Kip1 arrests neuroblastoma cell growth. Med Pediatr Oncol. 2001; 36(1):97-9. DOI: 10.1002/1096-911X(20010101)36:1<97::AID-MPO1022>3.0.CO;2-X. View

Tury A, Mairet-Coello G, DiCicco-Bloom E . The cyclin-dependent kinase inhibitor p57Kip2 regulates cell cycle exit, differentiation, and migration of embryonic cerebral cortical precursors. Cereb Cortex. 2011; 21(8):1840-56. PMC: 3138513. DOI: 10.1093/cercor/bhq254. View

Fyrst H, Saba J . An update on sphingosine-1-phosphate and other sphingolipid mediators. Nat Chem Biol. 2010; 6(7):489-97. PMC: 3001344. DOI: 10.1038/nchembio.392. View

Phan C, David P, Naidu M, Wong K, Sabaratnam V . Neurite outgrowth stimulatory effects of culinary-medicinal mushrooms and their toxicity assessment using differentiating Neuro-2a and embryonic fibroblast BALB/3T3. BMC Complement Altern Med. 2013; 13:261. PMC: 3852280. DOI: 10.1186/1472-6882-13-261. View

Li Z, Hailemariam T, Zhou H, Li Y, Duckworth D, Peake D . Inhibition of sphingomyelin synthase (SMS) affects intracellular sphingomyelin accumulation and plasma membrane lipid organization. Biochim Biophys Acta. 2007; 1771(9):1186-94. PMC: 2712822. DOI: 10.1016/j.bbalip.2007.05.007. View

Viglietto G, Motti M, Bruni P, Melillo R, DAlessio A, Califano D . Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med. 2002; 8(10):1136-44. DOI: 10.1038/nm762. View

Chen Q, Jin M, Yang F, Zhu J, Xiao Q, Zhang L . Matrix metalloproteinases: inflammatory regulators of cell behaviors in vascular formation and remodeling. Mediators Inflamm. 2013; 2013:928315. PMC: 3694547. DOI: 10.1155/2013/928315. View

10.

Godin J, Nguyen L . Novel functions of core cell cycle regulators in neuronal migration. Adv Exp Med Biol. 2013; 800:59-74. DOI: 10.1007/978-94-007-7687-6_4. View

11.

Baldassarre G, Belletti B, Nicoloso M, Schiappacassi M, Vecchione A, Spessotto P . p27(Kip1)-stathmin interaction influences sarcoma cell migration and invasion. Cancer Cell. 2005; 7(1):51-63. DOI: 10.1016/j.ccr.2004.11.025. View

12.

Malemud C . Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci. 2005; 11:1696-701. DOI: 10.2741/1915. View

13.

Frank C, Tsai L . Alternative functions of core cell cycle regulators in neuronal migration, neuronal maturation, and synaptic plasticity. Neuron. 2009; 62(3):312-26. PMC: 2757047. DOI: 10.1016/j.neuron.2009.03.029. View

14.

Nguyen L, Besson A, Heng J, Schuurmans C, Teboul L, Parras C . p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex. Genes Dev. 2006; 20(11):1511-24. PMC: 1475763. DOI: 10.1101/gad.377106. View

15.

Gusain A, Hatcher J, Adibhatla R, Wesley U, Dempsey R . Anti-proliferative effects of tricyclodecan-9-yl-xanthogenate (D609) involve ceramide and cell cycle inhibition. Mol Neurobiol. 2012; 45(3):455-64. PMC: 3381991. DOI: 10.1007/s12035-012-8254-0. View

16.

Burns T, Subathra M, Signorelli P, Choi Y, Yang X, Wang Y . Sphingomyelin synthase 1 activity is regulated by the BCR-ABL oncogene. J Lipid Res. 2012; 54(3):794-805. PMC: 3617953. DOI: 10.1194/jlr.M033985. View

17.

Lenglet S, Montecucco F, Mach F . Role of matrix metalloproteinases in animal models of ischemic stroke. Curr Vasc Pharmacol. 2013; 13(2):161-6. DOI: 10.2174/15701611113116660161. View

18.

Abdel Shakor A, Taniguchi M, Kitatani K, Hashimoto M, Asano S, Hayashi A . Sphingomyelin synthase 1-generated sphingomyelin plays an important role in transferrin trafficking and cell proliferation. J Biol Chem. 2011; 286(41):36053-36062. PMC: 3195583. DOI: 10.1074/jbc.M111.228593. View

19.

Reagan-Shaw S, Ahmad N . RNA interference-mediated depletion of phosphoinositide 3-kinase activates forkhead box class O transcription factors and induces cell cycle arrest and apoptosis in breast carcinoma cells. Cancer Res. 2006; 66(2):1062-9. DOI: 10.1158/0008-5472.CAN-05-1018. View

20.

Tafesse F, Ternes P, Holthuis J . The multigenic sphingomyelin synthase family. J Biol Chem. 2006; 281(40):29421-5. DOI: 10.1074/jbc.R600021200. View