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Turning Death to Growth: Hematopoietic Growth Factors Promote Neurite Outgrowth through MEK/ERK/p53 Pathway

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Abstract

Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) are the essential hematopoietic growth factors to control hematopoiesis. However, the role of SCF and G-CSF in the central nervous system remains poorly understood. Here, we have demonstrated the involvement of MEK/ERK/p53 signaling in SCF + G-CSF-enhanced neurite extension. Cortical neurons dissected from embryonic rat brains were seeded onto the membranes of transwell inserts, and neurite outgrowth was determined by using both the neurite outgrowth quantification assay kit and immunostaining of β III tubulin. Quantitative RT-PCR and western blotting were used for determining gene and protein expression of ERK and p53, respectively. p53 small interfering RNA (siRNAs) were introduced into neurons for examining the involvement of p53 in SCF + G-CSF-mediated neurite outgrowth. We observed that both SCF and G-CSF alone increased activation of MEK/ERK and gene expression of p53, while SCF + G-CSF synergistically activated the MEK/ERK signaling and upregulated p53 expression. MEK specific inhibitors (PD98059 and U0126) blocked the SCF + G-CSF-increased ERK phosphorylation and p53 gene and protein expression, and the MEK specific inhibitors also eliminated the SCF + G-CSF-promoted neurite outgrowth. p53 siRNAs knocked down the SCF + G-CSF-elevated p53 protein and prevented the SCF + G-CSF-enhanced neurite outgrowth. These findings suggest that activation of MEK/ERK/p53 signaling is required for SCF + G-CSF-promoted neurite outgrowth. Through the pro-apoptotic pathway of the MEK/ERK/p53, SCF + G-CSF turns neuronal fate from apoptotic commitment toward neural network generation. This observation provides novel insights into the putative role of SCF + G-CSF in supporting generation of neural connectivity during CNS development and in brain repair under pathological or neurodegenerative conditions.

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References

  1. Welte K, Platzer E, Lu L, Gabrilove JL, Levi E, Mertelsmann R, Moore MA (1985) Purification and biochemical characterization of human pluripotent hematopoietic colony-stimulating factor. Proc Natl Acad Sci U S A 82(5):1526–1530

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Zsebo KM, Wypych J, McNiece IK, HS L, Smith KA, Karkare SB, Sachdev RK, Yuschenkoff VN et al (1990) Identification, purification, and biological characterization of hematopoietic stem cell factor from buffalo rat liver—conditioned medium. Cell 63(1):195–201

    Article  PubMed  CAS  Google Scholar 

  3. McNiece IK, Briddell RA (1995) Stem cell factor. J Leukoc Biol 58(1):14–22

    Article  PubMed  CAS  Google Scholar 

  4. Ulich TR, del Castillo J, McNiece IK, Yi ES, Alzona CP, Yin SM, Zsebo KM (1991) Stem cell factor in combination with granulocyte colony-stimulating factor (CSF) or granulocyte-macrophage CSF synergistically increases granulopoiesis in vivo. Blood 78(8):1954–1962

    PubMed  CAS  Google Scholar 

  5. Molineux G, Migdalska A, Szmitkowski M, Zsebo K, Dexter TM (1991) The effects on hematopoiesis of recombinant stem cell factor (ligand for c-kit) administered in vivo to mice either alone or in combination with granulocyte colony-stimulating factor. Blood 78(4):961–966

    PubMed  CAS  Google Scholar 

  6. Broxmeyer HE, Lu L, Cooper S, Ruggieri L, Li ZH, Lyman SD (1995) Flt3 ligand stimulates/costimulates the growth of myeloid stem/progenitor cells. Exp Hematol 23(10):1121–1129

    PubMed  CAS  Google Scholar 

  7. McNiece IK, Langley KE, Zsebo KM (1991) Recombinant human stem cell factor synergises with GM-CSF, G-CSF, IL-3 and epo to stimulate human progenitor cells of the myeloid and erythroid lineages. Exp Hematol 19(3):226–231

    PubMed  CAS  Google Scholar 

  8. Fehniger TA, Carson WE, Mrozek E, Caligiuri MA (1997) Stem cell factor enhances interleukin-2-mediated expansion of murine natural killer cells in vivo. Blood 90(9):3647–3653

    PubMed  CAS  Google Scholar 

  9. Ulich TR, Yi ES, Yin S, del Castillo J, McNiece I, Yung YP, Zsebo KM (1993) Hematologic effects of stem cell factor alone and in combination with G-CSF and GM-CSF in vivo and in vitro in rodents. Int Rev Exp Pathol 34(Pt A):215–233

    PubMed  Google Scholar 

  10. Wang T, Alam R, Langley KE, Klimpel GR (2000) Stem cell factor and IL-2 act synergistically in inducing intraepithelial lymphocyte proliferation and cytokine production: upregulation of the IL-2 receptor gamma-chain and signaling via JAK-3. Cell Immunol 205(1):62–71. https://doi.org/10.1006/cimm.2000.1707

    Article  PubMed  CAS  Google Scholar 

  11. Duarte RF, Franf DA (2002) The synergy between stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF): molecular basis and clinical relevance. Leuk Lymphoma 43(6):1179–1187. https://doi.org/10.1080/10428190290026231

    Article  PubMed  CAS  Google Scholar 

  12. Andrews RG, Briddell RA, Knitter GH, Rowley SD, Appelbaum FR, McNiece IK (1995) Rapid engraftment by peripheral blood progenitor cells mobilized by recombinant human stem cell factor and recombinant human granulocyte colony-stimulating factor in nonhuman primates. Blood 85(1):15–20

    PubMed  CAS  Google Scholar 

  13. Briddell RA, Hartley CA, Smith KA, McNiece IK (1993) Recombinant rat stem cell factor synergizes with recombinant human granulocyte colony-stimulating factor in vivo in mice to mobilize peripheral blood progenitor cells that have enhanced repopulating potential. Blood 82(6):1720–1723

    PubMed  CAS  Google Scholar 

  14. To LB, Bashford J, Durrant S, MacMillan J, Schwarer AP, Prince HM, Gibson J, Lewis I et al (2003) Successful mobilization of peripheral blood stem cells after addition of ancestim (stem cell factor) in patients who had failed a prior mobilization with filgrastim (granulocyte colony-stimulating factor) alone or with chemotherapy plus filgrastim. Bone Marrow Transplant 31(5):371–378. https://doi.org/10.1038/sj.bmt.1703860

    Article  PubMed  CAS  Google Scholar 

  15. Hess DA, Levac KD, Karanu FN, Rosu-Myles M, White MJ, Gallacher L, Murdoch B, Keeney M et al (2002) Functional analysis of human hematopoietic repopulating cells mobilized with granulocyte colony-stimulating factor alone versus granulocyte colony-stimulating factor in combination with stem cell factor. Blood 100(3):869–878

    Article  PubMed  CAS  Google Scholar 

  16. Schneider A, Kruger C, Steigleder T, Weber D, Pitzer C, Laage R, Aronowski J, Maurer MH et al (2005) The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 115(8):2083–2098. https://doi.org/10.1172/JCI23559

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Zhao LR, Singhal S, Duan WM, Mehta J, Kessler JA (2007) Brain repair by hematopoietic growth factors in a rat model of stroke. Stroke 38(9):2584–2591. https://doi.org/10.1161/STROKEAHA.106.476457

    Article  PubMed  Google Scholar 

  18. Jin K, Mao XO, Sun Y, Xie L, Greenberg DA (2002) Stem cell factor stimulates neurogenesis in vitro and in vivo. J Clin Invest 110(3):311–319. https://doi.org/10.1172/JCI15251

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Piao CS, Li B, Zhang LJ, Zhao LR (2012) Stem cell factor and granulocyte colony-stimulating factor promote neuronal lineage commitment of neural stem cells. Differ Res Biol Divers 83(1):17–25. https://doi.org/10.1016/j.diff.2011.08.006

    Article  CAS  Google Scholar 

  20. Su Y, Cui L, Piao C, Li B, Zhao LR (2013) The effects of hematopoietic growth factors on neurite outgrowth. PLoS One 8(10):e75562. https://doi.org/10.1371/journal.pone.0075562

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Zhao LR, Navalitloha Y, Singhal S, Mehta J, Piao CS, Guo WP, Kessler JA, Groothuis DR (2007) Hematopoietic growth factors pass through the blood-brain barrier in intact rats. Exp Neurol 204(2):569–573. https://doi.org/10.1016/j.expneurol.2006.12.001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Hirata T, Morii E, Morimoto M, Kasugai T, Tsujimura T, Hirota S, Kanakura Y, Nomura S et al (1993) Stem cell factor induces outgrowth of c-kit-positive neurites and supports the survival of c-kit-positive neurons in dorsal root ganglia of mouse embryos. Development 119(1):49–56

    PubMed  CAS  Google Scholar 

  23. Carnahan JF, Patel DR, Miller JA (1994) Stem cell factor is a neurotrophic factor for neural crest-derived chick sensory neurons. J Neurosci 14(3 Pt 2):1433–1440

    Article  PubMed  CAS  Google Scholar 

  24. Dhandapani KM, Wade FM, Wakade C, Mahesh VB, Brann DW (2005) Neuroprotection by stem cell factor in rat cortical neurons involves AKT and NFkappaB. J Neurochem 95(1):9–19. https://doi.org/10.1111/j.1471-4159.2005.03319.x

    Article  PubMed  CAS  Google Scholar 

  25. Six I, Gasan G, Mura E, Bordet R (2003) Beneficial effect of pharmacological mobilization of bone marrow in experimental cerebral ischemia. Eur J Pharmacol 458(3):327–328

    Article  PubMed  CAS  Google Scholar 

  26. Gibson CL, Bath PM, Murphy SP (2005) G-CSF reduces infarct volume and improves functional outcome after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 25(4):431–439. https://doi.org/10.1038/sj.jcbfm.9600033

    Article  PubMed  CAS  Google Scholar 

  27. Komine-Kobayashi M, Zhang N, Liu M, Tanaka R, Hara H, Osaka A, Mochizuki H, Mizuno Y et al (2006) Neuroprotective effect of recombinant human granulocyte colony-stimulating factor in transient focal ischemia of mice. J Cereb Blood Flow Metab 26(3):402–413. https://doi.org/10.1038/sj.jcbfm.9600195

    Article  PubMed  CAS  Google Scholar 

  28. Kawada H, Takizawa S, Takanashi T, Morita Y, Fujita J, Fukuda K, Takagi S, Okano H et al (2006) Administration of hematopoietic cytokines in the subacute phase after cerebral infarction is effective for functional recovery facilitating proliferation of intrinsic neural stem/progenitor cells and transition of bone marrow-derived neuronal cells. Circulation 113(5):701–710. https://doi.org/10.1161/CIRCULATIONAHA.105.563668

    Article  PubMed  CAS  Google Scholar 

  29. Hirata T, Kasugai T, Morii E, Hirota S, Nomura S, Fujisawa H, Kitamura Y (1995) Characterization of c-kit-positive neurons in the dorsal root ganglion of mouse. Brain Res Dev Brain Res 85(2):201–211

    Article  PubMed  CAS  Google Scholar 

  30. Motro B, Wojtowicz JM, Bernstein A, van der Kooy D (1996) Steel mutant mice are deficient in hippocampal learning but not long-term potentiation. Proc Natl Acad Sci U S A 93(5):1808–1813

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Katafuchi T, Li AJ, Hirota S, Kitamura Y, Hori T (2000) Impairment of spatial learning and hippocampal synaptic potentiation in c-kit mutant rats. Learn Mem 7(6):383–392

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Diederich K, Sevimli S, Dorr H, Kosters E, Hoppen M, Lewejohann L, Klocke R, Minnerup J et al (2009) The role of granulocyte-colony stimulating factor (G-CSF) in the healthy brain: a characterization of G-CSF-deficient mice. J Neurosci 29(37):11572–11581. https://doi.org/10.1523/JNEUROSCI.0453-09.2009

    Article  PubMed  CAS  Google Scholar 

  33. Zhao LR, Berra HH, Duan WM, Singhal S, Mehta J, Apkarian AV, Kessler JA (2007) Beneficial effects of hematopoietic growth factor therapy in chronic ischemic stroke in rats. Stroke 38(10):2804–2811. https://doi.org/10.1161/STROKEAHA.107.486217

    Article  PubMed  CAS  Google Scholar 

  34. Cui L, Murikinati SR, Wang D, Zhang X, Duan WM, Zhao LR (2013) Reestablishing neuronal networks in the aged brain by stem cell factor and granulocyte-colony stimulating factor in a mouse model of chronic stroke. PLoS One 8(6):e64684. https://doi.org/10.1371/journal.pone.0064684

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Cui L, Wang D, McGillis S, Kyle M, Zhao LR (2016) Repairing the brain by SCF+G-CSF treatment at 6 months Postexperimental stroke: mechanistic determination of the causal link between neurovascular regeneration and motor functional recovery. ASN Neuro 8(4). doi:https://doi.org/10.1177/1759091416655010

  36. Cui L, Duchamp NS, Boston DJ, Ren X, Zhang X, Hu H, Zhao LR (2015) NF-kappaB is involved in brain repair by stem cell factor and granulocyte-colony stimulating factor in chronic stroke. Exp Neurol 263:17–27. https://doi.org/10.1016/j.expneurol.2014.08.026

    Article  PubMed  CAS  Google Scholar 

  37. Watanabe H, Yokozeki T, Yamazaki M, Miyazaki H, Sasaki T, Maehama T, Itoh K, Frohman MA et al (2004) Essential role for phospholipase D2 activation downstream of ERK MAP kinase in nerve growth factor-stimulated neurite outgrowth from PC12 cells. J Biol Chem 279(36):37870–37877. https://doi.org/10.1074/jbc.M402610200

    Article  PubMed  CAS  Google Scholar 

  38. Heiser JH, Schuwald AM, Sillani G, Ye L, Muller WE, Leuner K (2013) TRPC6 channel-mediated neurite outgrowth in PC12 cells and hippocampal neurons involves activation of RAS/MEK/ERK, PI3K, and CAMKIV signaling. J Neurochem 127(3):303–313. https://doi.org/10.1111/jnc.12376

    Article  PubMed  CAS  Google Scholar 

  39. Zhang K, Duan L, Ong Q, Lin Z, Varman PM, Sung K, Cui B (2014) Light-mediated kinetic control reveals the temporal effect of the Raf/MEK/ERK pathway in PC12 cell neurite outgrowth. PLoS One 9(3):e92917. https://doi.org/10.1371/journal.pone.0092917

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Li M, Li S, Li Y (2015) Liraglutide promotes cortical neurite outgrowth via the MEK-ERK pathway. Cell Mol Neurobiol 35(7):987–993. https://doi.org/10.1007/s10571-015-0193-7

    Article  PubMed  CAS  Google Scholar 

  41. Jorgensen JR, Fransson A, Fjord-Larsen L, Thompson LH, Houchins JP, Andrade N, Torp M, Kalkkinen N et al (2012) Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo. Exp Neurol 233(1):172–181. https://doi.org/10.1016/j.expneurol.2011.09.027

    Article  PubMed  CAS  Google Scholar 

  42. Miranda MB, Xu H, Torchia JA, Johnson DE (2005) Cytokine-induced myeloid differentiation is dependent on activation of the MEK/ERK pathway. Leuk Res 29(11):1293–1306. https://doi.org/10.1016/j.leukres.2005.03.016

    Article  PubMed  CAS  Google Scholar 

  43. Kumar P, Wu H, McBride JL, Jung KE, Kim MH, Davidson BL, Lee SK, Shankar P et al (2007) Transvascular delivery of small interfering RNA to the central nervous system. Nature 448(7149):39–43. https://doi.org/10.1038/nature05901

    Article  PubMed  CAS  Google Scholar 

  44. Mruthyunjaya S, Rumma M, Ravibhushan G, Anjali S, Padma S (2011) C-Jun/AP-1 transcription factor regulates laminin-1-induced neurite outgrowth in human bone marrow mesenchymal stem cells: role of multiple signaling pathways. FEBS Lett 585(12):1915–1922. https://doi.org/10.1016/j.febslet.2011.04.072

    Article  PubMed  CAS  Google Scholar 

  45. White DM, Walker S, Brenneman DE, Gozes I (2000) CREB contributes to the increased neurite outgrowth of sensory neurons induced by vasoactive intestinal polypeptide and activity-dependent neurotrophic factor. Brain Res 868(1):31–38

    Article  PubMed  CAS  Google Scholar 

  46. Seow KH, Zhou L, Stephanopoulos G, Too HP (2013) C-Jun N-terminal kinase in synergistic neurite outgrowth in PC12 cells mediated through P90RSK. BMC Neurosci 14:153. https://doi.org/10.1186/1471-2202-14-153

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Shmueli O, Gdalyahu A, Sorokina K, Nevo E, Avivi A, Reiner O (2001) DCX in PC12 cells: CREB-mediated transcription and neurite outgrowth. Hum Mol Genet 10(10):1061–1070

    Article  PubMed  CAS  Google Scholar 

  48. Steinshamn S, Bergh K, Waage A (1993) Effects of stem cell factor and granulocyte colony-stimulating factor on granulocyte recovery and Candida albicans infection in granulocytopenic mice. J Infect Dis 168(6):1444–1448

    Article  PubMed  CAS  Google Scholar 

  49. Shaul YD, Seger R (2007) The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta 1773(8):1213–1226. https://doi.org/10.1016/j.bbamcr.2006.10.005

    Article  PubMed  CAS  Google Scholar 

  50. Liu X, Wang X, Lu J (2015) Tenuifoliside A promotes neurite outgrowth in PC12 cells via the PI3K/AKT and MEK/ERK/CREB signaling pathways. Mol Med Rep 12(5):7637–7642. https://doi.org/10.3892/mmr.2015.4397

    Article  PubMed  CAS  Google Scholar 

  51. Wang X, Wang Z, Yao Y, Li J, Zhang X, Li C, Cheng Y, Ding G et al (2011) Essential role of ERK activation in neurite outgrowth induced by alpha-lipoic acid. Biochim Biophys Acta 1813(5):827–838. https://doi.org/10.1016/j.bbamcr.2011.01.027

    Article  PubMed  CAS  Google Scholar 

  52. Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH et al (1989) Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244(4901):217–221

    Article  PubMed  CAS  Google Scholar 

  53. el-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW, Vogelstein B (1992) Definition of a consensus binding site for p53. Nat Genet 1(1):45–49. https://doi.org/10.1038/ng0492-45

    Article  PubMed  CAS  Google Scholar 

  54. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253(5015):49–53

    Article  PubMed  CAS  Google Scholar 

  55. Lane DP (1992) Cancer. p53, guardian of the genome. Nature 358(6381):15–16. https://doi.org/10.1038/358015a0

    Article  PubMed  CAS  Google Scholar 

  56. Li YQ, Cheng ZC, Liu SW, Aubert I, Wong CS (2016) P53 regulates disruption of neuronal development in the adult hippocampus after irradiation. Cell Death Discov 2:16072. https://doi.org/10.1038/cddiscovery.2016.72

    Article  PubMed  PubMed Central  Google Scholar 

  57. Bartesaghi S, Graziano V, Galavotti S, Henriquez NV, Betts J, Saxena J, Minieri V, A D KA et al (2015) Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells. Proc Natl Acad Sci U S A 112(4):1059–1064. https://doi.org/10.1073/pnas.1413165112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2(8):594–604. https://doi.org/10.1038/nrc864

    Article  PubMed  CAS  Google Scholar 

  59. Armstrong JF, Kaufman MH, Harrison DJ, Clarke AR (1995) High-frequency developmental abnormalities in p53-deficient mice. Curr Biol 5(8):931–936

    Article  PubMed  CAS  Google Scholar 

  60. Ostrakhovitch EA, Semenikhin OA (2011) p53-mediated regulation of neuronal differentiation via regulation of dual oxidase maturation factor 1. Neurosci Lett 494(1):80–85. https://doi.org/10.1016/j.neulet.2011.02.061

    Article  PubMed  CAS  Google Scholar 

  61. Quadrato G, Di Giovanni S (2012) Gatekeeper between quiescence and differentiation: p53 in axonal outgrowth and neurogenesis. Int Rev Neurobiol 105:71–89. https://doi.org/10.1016/B978-0-12-398309-1.00005-6

    Article  PubMed  CAS  Google Scholar 

  62. Di Giovanni S, Rathore K (2012) p53-dependent pathways in neurite outgrowth and axonal regeneration. Cell Tissue Res 349(1):87–95. https://doi.org/10.1007/s00441-011-1292-5

    Article  PubMed  CAS  Google Scholar 

  63. Xavier JM, Morgado AL, Sola S, Rodrigues CM (2014) Mitochondrial translocation of p53 modulates neuronal fate by preventing differentiation-induced mitochondrial stress. Antioxid Redox Signal 21(7):1009–1024. https://doi.org/10.1089/ars.2013.5417

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Charni M, Aloni-Grinstein R, Molchadsky A, Rotter V (2017) p53 on the crossroad between regeneration and cancer. Cell Death Differ 24(1):8–14. https://doi.org/10.1038/cdd.2016.117

    Article  PubMed  CAS  Google Scholar 

  65. Di Giovanni S, Knights CD, Rao M, Yakovlev A, Beers J, Catania J, Avantaggiati ML, Faden AI (2006) The tumor suppressor protein p53 is required for neurite outgrowth and axon regeneration. EMBO J 25(17):4084–4096. https://doi.org/10.1038/sj.emboj.7601292

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Zhang J, Yan W, Chen X (2006) p53 is required for nerve growth factor-mediated differentiation of PC12 cells via regulation of TrkA levels. Cell Death Differ 13(12):2118–2128. https://doi.org/10.1038/sj.cdd.4401972

    Article  PubMed  CAS  Google Scholar 

  67. Tedeschi A, Nguyen T, Puttagunta R, Gaub P, Di Giovanni S (2009) A p53-CBP/p300 transcription module is required for GAP-43 expression, axon outgrowth, and regeneration. Cell Death Differ 16(4):543–554. https://doi.org/10.1038/cdd.2008.175

    Article  PubMed  CAS  Google Scholar 

  68. Eizenberg O, Faber-Elman A, Gottlieb E, Oren M, Rotter V, Schwartz M (1996) p53 plays a regulatory role in differentiation and apoptosis of central nervous system-associated cells. Mol Cell Biol 16(9):5178–5185

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Qin Q, Baudry M, Liao G, Noniyev A, Galeano J, Bi X (2009) A novel function for p53: regulation of growth cone motility through interaction with rho kinase. J Neurosci 29(16):5183–5192. https://doi.org/10.1523/JNEUROSCI.0420-09.2009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Liu Y, Chen Y, Lu X, Wang Y, Duan Y, Cheng C, Shen A (2012) SCYL1BP1 modulates neurite outgrowth and regeneration by regulating the Mdm2/p53 pathway. Mol Biol Cell 23(23):4506–4514. https://doi.org/10.1091/mbc.E12-05-0362

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Gaub P, Joshi Y, Wuttke A, Naumann U, Schnichels S, Heiduschka P, Di Giovanni S (2011) The histone acetyltransferase p300 promotes intrinsic axonal regeneration. Brain 134(Pt 7):2134–2148. https://doi.org/10.1093/brain/awr142

    Article  PubMed  Google Scholar 

  72. Joshi Y, Soria MG, Quadrato G, Inak G, Zhou L, Hervera A, Rathore KI, Elnaggar M et al (2015) The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury. Brain 138(Pt 7):1843–1862. https://doi.org/10.1093/brain/awv125

    Article  PubMed  Google Scholar 

  73. Li DW, Liu JP, Mao YW, Xiang H, Wang J, Ma WY, Dong Z, Pike HM et al (2005) Calcium-activated RAF/MEK/ERK signaling pathway mediates p53-dependent apoptosis and is abrogated by alpha B-crystallin through inhibition of RAS activation. Mol Biol Cell 16(9):4437–4453. https://doi.org/10.1091/mbc.E05-01-0010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Bai JA, Xu GF, Yan LJ, Zeng WW, Ji QQ, Wu JD, Tang QY (2015) SGK1 inhibits cellular apoptosis and promotes proliferation via the MEK/ERK/p53 pathway in colitis. World J Gastroenterol 21(20):6180–6193. https://doi.org/10.3748/wjg.v21.i20.6180

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgments

The authors acknowledge Sandra McGillis for her assistance with proofreading.

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This work was supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke (NIH/NINDS) (R01 NS060911).

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  1. Department of Neurosurgery, State University of New York Upstate Medical University, 750 E. Adams Street, Syracuse, NY, 13210, USA

    Mei Gao & Li-Ru Zhao

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Gao, M., Zhao, LR. Turning Death to Growth: Hematopoietic Growth Factors Promote Neurite Outgrowth through MEK/ERK/p53 Pathway. Mol Neurobiol 55, 5913–5925 (2018). https://doi.org/10.1007/s12035-017-0814-x

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