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Nuclear Akt promotes neurite outgrowth in the early stage of neuritogenesis

  • Park, Ji-Hye (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine) ;
  • Lee, Sang-Bae (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine) ;
  • Lee, Kyung-Hoon (Department of Anatomy, Sungkyunkwan University School of Medicine) ;
  • Ahn, Jee-Yin (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine)
  • Received : 2012.05.24
  • Accepted : 2012.06.04
  • Published : 2012.09.30

Abstract

In addition to its pivotal role in neuronal survival, PI3K/Akt signaling is integral to neuronal differentiation and neurite outgrowth. However, the exact role of Akt in neuronal differentiation is still controversial. Here, we found that nuclear expression of CA-Akt resulted in unusual rapid neurite outgrowth and overexpression of KD-Akt caused multiple dendrite growth without specific axon elongation. Moreover, microarray data revealed that the expression of FOXQ1 expression was about 10-fold higher in cells with nuclear, active Akt than in control cells. Quantitative real-time PCR analysis showed that mRNA levels were upregulated in NLS-CA-Akt cells as compared to KD or EV cells. Furthermore, our FACS analysis demonstrated that overexpression of NLS-CA-Akt accumulate cells in the G1 phase within 24 h, fitting with the rapid sprouting of neuritis. Thus, our data implied that at least in this early time frame, the overexpression of nuclear, active Akt forced cells into neurite development through probably FOXQ1regulation.

Keywords

References

  1. Brunet, A., Datta, S. R. and Greenberg, M. E. (2001) Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr. Opin. Neurobiol. 11, 297-305. https://doi.org/10.1016/S0959-4388(00)00211-7
  2. Jaworski, J., Spangler, S., Seeburg, D. P., Hoogenraad, C. C. and Sheng, M. (2005) Control of dendritic arborization by the phosphoinositide-3'-kinase-Akt-mammalian target of rapamycin pathway. J. Neurosci. 25, 11300-11312. https://doi.org/10.1523/JNEUROSCI.2270-05.2005
  3. Jiang, H. and Rao, Y. (2005) Axon formation: fate versus growth. Nat. Neurosci. 8, 544-546. https://doi.org/10.1038/nn0505-544
  4. Vanhaesebroeck, B., Leevers, S. J., Ahmadi, K., Timms, J., Katso, R., Driscoll, P. C., Woscholski, R., Parker, P. J. and Waterfield, M. D. (2001) Synthesis and function of 3-phosphorylated inositol lipids. Annu. Rev. Biochem. 70, 535-602. https://doi.org/10.1146/annurev.biochem.70.1.535
  5. Ahn, J. Y., Liu, X., Liu, Z., Pereira, L., Cheng, D., Peng, J., Wade, P. A., Hamburger, A. W. and Ye, K. (2006) Nuclear Akt associates with PKC-phosphorylated Ebp1, preventing DNA fragmentation by inhibition of caspase-activated DNase. EMBO J. 25, 2083-2095. https://doi.org/10.1038/sj.emboj.7601111
  6. Lee, S. B., Xuan Nguyen, T. L., Choi, J. W., Lee, K. H., Cho, S. W., Liu, Z., Ye, K., Bae, S. S. and Ahn, J. Y. (2008) Nuclear Akt interacts with B23/NPM and protects it from proteolytic cleavage, enhancing cell survival. Proc. Natl. Acad. Sci. U.S.A. 105, 16584-16589. https://doi.org/10.1073/pnas.0807668105
  7. Konishi, H., Namikawa, K., Shikata, K., Kobatake, Y., Tachibana, T. and Kiyama, H. (2007) Identification of peripherin as a Akt substrate in neurons. J. Biol. Chem. 282, 23491-23499. https://doi.org/10.1074/jbc.M611703200
  8. Enomoto, A., Murakami, H., Asai, N., Morone, N., Watanabe, T., Kawai, K., Murakumo, Y., Usukura, J., Kaibuchi, K. and Takahashi, M. (2005) Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev. Cell 9, 389-402. https://doi.org/10.1016/j.devcel.2005.08.001
  9. Zhou, F. Q., Zhou, J., Dedhar, S., Wu, Y. H. and Snider, W. D. (2004) NGF-induced axon growth is mediated by localized inactivation of GSK-3beta and functions of the microtubule plus end binding protein APC Neuron. 42, 897-912. https://doi.org/10.1016/j.neuron.2004.05.011
  10. Kimura, K., Hattori, S., Kabuyama, Y., Shizawa, Y., Takayanagi, J., Nakamura, S., Toki, S., Matsuda, Y., Onodera, K. and Fukui, Y. (1994) Neurite outgrowth of PC12 cells is suppressed by wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase. J. Biol. Chem. 269, 18961-18967.
  11. Mills, J., Digicaylioglu, M., Legg, A. T., Young, C. E., Young, S. S., Barr, A. M., Fletcher, L., O'Connor, T. P. and Dedhar, S. (2003) Role of integrin-linked kinase in nerve growth factor-stimulated neurite outgrowth. J. Neurosci. 23, 1638-1648.
  12. Namikawa, K., Honma, M., Abe, K., Takeda, M., Mansur, K., Obata, T., Miwa, A., Okado, H. and Kiyama, H. (2000) Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal regeneration. J. Neurosci. 20, 2875-2886.
  13. Bang, O. S., Park, E. K., Yang, S. I., Lee, S. R., Franke, T. F. and Kang, S. S. (2001) Overexpression of Akt inhibits NGF-induced growth arrest and neuronal differentiation of PC12 cells. J. Cell. Sci. 114, 81-88.
  14. Higuchi, M., Onishi, K., Masuyama, N. and Gotoh, Y. (2003) The phosphatidylinositol-3 kinase (PI3K)-Akt pathway suppresses neurite branch formation in NGF-treated PC12 cells. Genes Cells 8, 657-669. https://doi.org/10.1046/j.1365-2443.2003.00663.x
  15. Ooms, L. M., Fedele, C. G., Astle, M. V., Ivetac, I., Cheung, V., Pearson, R. B., Layton, M. J., Forrai, A., Nandurkar, H. H. and Mitchell, C. A. (2006) The inositol polyphosphate 5-phosphatase, PIPP, Is a novel regulator of phosphoinositide 3-kinase-dependent neurite elongation. Mol. Biol. Cell 17, 607-622.
  16. Ashcroft, M., Stephens, R. M., Hallberg, B., Downward, J. and Kaplan, D. R. (1999) The selective and inducible activation of endogenous PI 3-kinase in PC12 cells results in efficient NGF-mediated survival but defective neurite outgrowth. Oncogene. 18, 4586-4597. https://doi.org/10.1038/sj.onc.1202814
  17. Jiang, H., Guo, W., Liang, X. and Rao, Y. (2005) Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators. Cell 120, 123-135.
  18. Hoggatt, A. M., Kriegel, A. M., Smith, A. F. and Herring, B. P. (2000) Hepatocyte nuclear factor-3 homologue 1 (HFH-1) represses transcription of smooth muscle-specific genes. J. Biol. Chem. 275, 31162-31170. https://doi.org/10.1074/jbc.M005595200
  19. Martinez-Ceballos, E., Chambon, P. and Gudas, L. J. (2005) Differences in gene expression between wild type and Hoxa1 knockout embryonic stem cells after retinoic acid treatment or leukemia inhibitory factor (LIF) removal. J. Biol. Chem. 280, 16484-16498. https://doi.org/10.1074/jbc.M414397200
  20. Kaneda, H., Arao, T., Tanaka, K., Tamura, D., Aomatsu, K., Kudo, K., Sakai, K., De Velasco, M. A., Matsumoto, K., Fujita, Y., Yamada, Y., Tsurutani, J., Okamoto, I., Nakagawa, K. and Nishio, K. (2010) FOXQ1 is overexpressed in colorectal cancer and enhances tumorigenicity and tumor growth. Cancer Res. 70, 2053-2063. https://doi.org/10.1158/0008-5472.CAN-09-2161
  21. Ahn, J. Y., Rong, R., Liu, X. and Ye, K. (2004) PIKE/nuclear PI 3-kinase signaling mediates the antiapoptotic actions of NGF in the nucleus. EMBO J. 23, 3995-4006. https://doi.org/10.1038/sj.emboj.7600392
  22. Buchkovich, K. J. and Ziff, E. B. (1994) Nerve growth factor regulates the expression and activity of p33cdk2 and p34cdc2 kinases in PC12 pheochromocytoma cells. Mol. Biol. Cell. 5, 1225-1241. https://doi.org/10.1091/mbc.5.11.1225
  23. Burstein, D. E. and Greene, L. A. (1982) Nerve growth factor has both mitogenic and antimitogenic activity. Dev. Biol. 94, 477-482. https://doi.org/10.1016/0012-1606(82)90364-5
  24. Ignatius, M. J., Chandler, C. R. and Shooter, E. M. (1985) Nerve growth factor-treated, neurite-bearing PC12 cells continue to synthesize DNA. J. Neurosci. 5, 343-351.
  25. Nguyen Tle, X. and Ahn, J. Y. (2007) Lipase inactive mutant of PLC-gamma1 regulates NGF-induced neurite outgrowth via enzymatic activity and regulation of cell cycle regulatory proteins. J. Biochem. Mol. Biol. 40, 888-894. https://doi.org/10.5483/BMBRep.2007.40.6.888
  26. Rudkin, B. B., Lazarovici, P., Levi, B. Z., Abe, Y., Fujita, K. and Guroff, G. (1989) Cell cycle-specific action of nerve growth factor in PC12 cells: differentiation without proliferation. EMBO J. 8, 3319-3325.
  27. Arden, K. C. (2008) FOXO animal models reveal a variety of diverse roles for FOXO transcription factors. Oncogene. 27, 2345-2350. https://doi.org/10.1038/onc.2008.27
  28. Christensen, R., de la Torre-Ubieta, L., Bonni, A. and Colon-Ramos, D. A. (2011) A conserved PTEN/FOXO pathway regulates neuronal morphology during C. elegans development. Development 138, 5257-5267. https://doi.org/10.1242/dev.069062
  29. Rossig, L., Jadidi, A. S., Urbich, C., Badorff, C., Zeiher, A. M. and Dimmeler, S. (2001) Akt-dependent phosphorylation of p21(Cip1) regulates PCNA binding and proliferation of endothelial cells. Mol. Cell Biol. 21, 5644-5657. https://doi.org/10.1128/MCB.21.16.5644-5657.2001
  30. Harms, C., Albrecht, K., Harms, U., Seidel, K., Hauck, L., Baldinger, T., Hubner, D., Kronenberg, G., An, J., Ruscher, K., Meisel, A., Dirnagl, U., von Harsdorf, R., Endres, M. and Hortnagl, H. (2007) Phosphatidylinositol 3-Akt-kinase-dependent phosphorylation of p21 (Waf1/Cip1) as a novel mechanism of neuroprotection by glucocorticoids. J. Neurosci. 27, 4562-4571. https://doi.org/10.1523/JNEUROSCI.5110-06.2007
  31. Kwon, I. S., Lee, K. H., Choi, J. W. and Ahn, J. Y. (2010) PI(3,4,5)P3 regulates the interaction between Akt and B23 in the nucleus. BMB Rep. 43, 127-132. https://doi.org/10.5483/BMBRep.2010.43.2.127
  32. Cho, S. A., Seo, M. J., Ko, J. Y., Shim, J. H., Yoo, J., Kim, J. H., Kim, S. Y., Ryu, N. K., Park, E. Y., Lee, H. W., Lee, Y. S., Bahk, Y. Y. and Park, J. H. (2010) Up-regulation of Idh3$\alpha$ causes reduction of neuronal differentiation in PC12 cells. BMB Rep. 43, 369-374 https://doi.org/10.5483/BMBRep.2010.43.5.369

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