Skip to main content
SpringerLink
Log in

Overexpression of LIM Kinase 1 Renders Resistance to Apoptosis in PC12 Cells by Inhibition of Caspase Activation

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

LIM kinases (LIMKs) regulate actin polymerization by phosphorylating cofilin and are predominantly expressed in neural tissue. In this study, the effect of LIMK1 overexpression in PC12 cell apoptosis was investigated. PC12 cells overexpressing the wild-type LIMK1 were more resistant to serum-withdrawal-induced cell death and the level of caspase 3 activation in these cells was lower than in the control PC12 cells or than in the PC12 cells expressing a mutant LIMK1 lacking the kinase domain. The inhibition of JNK activation was observed in the PC12 cells overexpressing the wild-type LIMK1 after serum withdrawal. These results suggest that the LIMK1 might allow resistance to apoptosis in PC12 cells by inhibiting JNK activation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Abe, H., Obinata, T., Minamide, L. S., and Bamburg, J. R. (1996). Xenopus laevis actin-depolymerizing factor/cofilin: A phosphorylation-regulated protein essential for development. J. Cell Biol. 132: 871-885.

    Google Scholar 

  • Arber, S., Barbayannis, F. A., Hanser, H., Schneider, C., Stanyon, C. A., Bernard, O., and Caroni, P. (1998). Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 393: 805-809.

    Google Scholar 

  • Bernard, O., Ganiatsas, S., Kannourakis, G., and Dringen, R. (1994). Kiz-1, a protein with LIM zinc finger and kinase domains, is expressed mainly in neurons. Cell Growth Differ. 5: 1159-1171.

    Google Scholar 

  • Berra, E., Diaz-Meco, M. T., and Moscat, J. (1998). The activation of p38 and apoptosis by the inhibition of Erk is antagonized by the phosphoinositide 3-kinase/Akt pathway. J. Biol. Chem. 273: 10792-10797.

    Google Scholar 

  • Boulton, T. G., Nye, S. H., Robbins, D. J., Ip, N. Y., Radziejewska, E., Morgenbesser, S. D., DePinho, R. A., Panayotatos, N., Cobb, M. H., and Yancopoulos, G. D. (1991). ERKs: A family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65: 663-675.

    Google Scholar 

  • Cahill, M. A., Peter, M. E., Kischkel, F. C., Chinnaiyan, A. M., Dixit, V. M., Krammer, P. H., and Nordheim, A. (1996). CD95 (APO-1/Fas) induces activation of SAP kinases downstream of ICE-like proteases. Oncogene 13: 2087-2096.

    Google Scholar 

  • Cardone, M. H., Salvesen, G. S., Widmann, C., Johnson, G., and Frisch, S. M. (1997). The regulation of anoikis: MEKK-1 activation requires cleavage by caspases. Cell 90: 315-323.

    Google Scholar 

  • Chen, Y. R., Wang, X., Templeton, D., Davis, R. J., and Tan, T. H. (1996). The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. J. Biol. Chem. 271: 31929-31936.

    Google Scholar 

  • Cobb, M. H., Robbins, D. J., and Boulton, T. G. (1991). ERKs, extracellular signal-regulated MAP-2 kinases. Curr. Opin. Cell Biol. 3: 1025-1032.

    Google Scholar 

  • Conrad, P. W., Rust, R. T., Han, J., Millhorn, D. E., and Beitner-Johnson, D. (1999). Selective activation of p38alpha and p38gamma by hypoxia. Role in regulation of cyclin D1 by hypoxia in PC12 cells. J. Biol. Chem. 274: 23570-23576.

    Google Scholar 

  • Davis, R. J. (1993). The mitogen-activated protein kinase signal transduction pathway. J. Biol. Chem. 268: 14553-14556.

    Google Scholar 

  • Davis, R. J. (1994). MAPKs: New JNK expands the group. Trends Biochem. Sci. 19: 470-473.

    Google Scholar 

  • Derijard, B., Hibi, M., Wu, I. H., Barrett, T., Su, B., Deng, T., Karin, M., and Davis, R. J. (1994). JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76: 1025-1037.

    Google Scholar 

  • Graves, J. D., Draves, K. E., Craxton, A., Saklatvala, J., Krebs, E. G., and Clark, E. A. (1996). Involvement of stress-activated protein kinase and p38 mitogen-activated protein kinase in mIgM-induced apoptosis of human B lymphocytes. Proc. Natl. Acad. Sci. U.S.A. 93: 13814-13818.

    Google Scholar 

  • Guyton, K. Z., Liu, Y., Gorospe, M., Xu, Q., and Holbrook, N. J. (1996). Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury. J. Biol. Chem. 271: 4138-4142.

    Google Scholar 

  • Han, O. J., Joe, K. H., Kim, S. W., Lee, H. S., Kwon, N. S., Baek, K. J., and Yun, H. Y. (2001). Involvement of p38 mitogen-activated protein kinase and apoptosis signal-regulating kinase-1 in nitric oxide-induced cell death in PC12 cells. Neurochem. Res. 26: 525-532.

    Google Scholar 

  • Horstmann, S., Kahle, P. J., and Borasio, G. D. (1998). Inhibitors of p38 mitogen-activated protein kinase promote neuronal survival in vitro. J. Neurosci. Res. 52: 483-490.

    Google Scholar 

  • Ikebe, C., Ohashi, K., Fujimori, T., Bernard, O., Noda, T., Robertson, E. J., and Mizuno, K. (1997). Mouse LIM-kinase 2 gene: cDNA cloning, genomic organization, and tissue-specific expression of two alternatively initiated transcripts. Genomics 46: 504-508.

    Google Scholar 

  • Juo, P., Kuo, C. J., Reynolds, S. E., Konz, R. F., Raingeaud, J., Davis, R. J., Biemann, H. P., and Blenis, J. (1997). Fas activation of the p38 mitogen-activated protein kinase signalling pathway requires ICE/CED-3 family proteases. Mol. Cell. Biol. 17: 24-35.

    Google Scholar 

  • Koshimizu, U., Takahashi, H., Yoshida, M. C., and Nakamura, T. (1997). cDNA cloning, genomic organization, and chromosomal localization of the mouse LIM motif-containing kinase gene, Limk2. Biochem. Biophys. Res. Commun. 241: 243-250.

    Google Scholar 

  • Meberg, P. J., Ono, S., Minamide, L. S., Takahashi, M., and Bamburg, J. R. (1998). Actin depolymerizing factor and cofilin phosphorylation dynamics: Response to signals that regulate neurite extension. Cell Motil. Cytoskeleton 39: 172-190.

    Google Scholar 

  • Mills, J. C., Stone, N. L., and Pittman, R. N. (1999). Extranuclear apoptosis. The role of the cytoplasm in the execution phase. J. Cell Biol. 146: 703-708.

    Google Scholar 

  • Mizuno, K., Okano, I., Ohashi, K., Nunoue, K., Kuma, K., Miyata, T., and Nakamura, T. (1994). Identification of a human cDNA encoding a novel protein kinase with two repeats of the LIM/double zinc finger motif. Oncogene 9: 1605-1612.

    Google Scholar 

  • Mori, T., Okano, I., Mizuno, K., Tohyama, M., and Wanaka, A. (1997). Comparison of tissue distribution of two novel serine/threonine kinase genes containing the LIM motif (LIMK-1 and LIMK-2) in the developing rat. Brain Res. Mol. Brain Res. 45: 247-254.

    Google Scholar 

  • Muhlenbeck, F., Haas, E., Schwenzer, R., Schubert, G., Grell, M., Smith, C., Scheurich, P., and Wajant, H. (1998). TRAIL/Apo2L activates c-Jun NH2-terminal kinase (JNK) via caspase-dependent and caspase-independent pathways. J. Biol. Chem. 273: 33091-33098.

    Google Scholar 

  • Namgung, U., and Xia, Z. (2001). Arsenic induces apoptosis in rat cerebellar neurons via activation of JNK3 and p38 MAP kinases. Toxicol. Appl. Pharmacol. 174: 130-138.

    Google Scholar 

  • Nath, R., McGinnis, K., Dutta, S., Shivers, B., and Wang, K. K. (2001). Inhibition of p38 kinase mimics survival signal-linked protection against apoptosis in rat cerebellar granule neurons. Cell Mol. Biol. Lett. 6: 173-184.

    Google Scholar 

  • Nunoue, K., Ohashi, K., Okano, I., and Mizuno, K. (1995). LIMK-1 and LIMK-2, two members of a LIM motif-containing protein kinase family. Oncogene 11: 701-710.

    Google Scholar 

  • Okano, I., Hiraoka, J., Otera, H., Nunoue, K., Ohashi, K., Iwashita, S., Hirai, M., and Mizuno, K. (1995). Identification and characterization of a novel family of serine/threonine kinases containing two N-terminal LIM motifs. J. Biol. Chem. 270: 31321-31330.

    Google Scholar 

  • Parlato, S., Giammarioli, A. M., Logozzi, M., Lozupone, F., Matarrese, P., Luciani, F., Falchi, M., Malorni, W., and Fais, S. (2000). CD95 (APO-1/Fas) linkage to the actin cytoskeleton through ezrin in human T lymphocytes: A novel regulatory mechanism of the CD95 apoptotic pathway. EMBO J. 19: 5123-5134.

    Google Scholar 

  • Posey, S. C., and Bierer, B. E. (1999). Actin stabilization by jasplakinolide enhances apoptosis induced by cytokine deprivation. J. Biol. Chem. 274: 4259-4265.

    Google Scholar 

  • Rosen, K., Rak, J., Leung, T., Dean, N. M., Kerbel, R. S., and Filmus, J. (2000). Activated Ras prevents downregulation of Bcl-X(L) triggered by detachment from the extracellular matrix. A mechanism of Ras-induced resistance to anoikis in intestinal epithelial cells. J. Cell Biol. 149: 447-456.

    Google Scholar 

  • Roth, J. A., Feng, L., Walowitz, J., and Browne, R. W. (2000). Manganese-induced rat pheochromocytoma (PC12) cell death is independent of caspase activation. J. Neurosci. Res. 61: 162-171.

    Google Scholar 

  • Sarker, K. P., Nakata, M., Kitajima, I., Nakajima, T., and Maruyama, I. (2000). Inhibition of caspase-3 activation by SB 203580, p38 mitogen-activated protein kinase inhibitor in nitric oxide-induced apoptosis of PC-12 cells. J. Mol. Neurosci. 15: 243-250.

    Google Scholar 

  • Sumi, T., Matsumoto, K., Shibuya, A., and Nakamura, T. (2001). Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha. J. Biol. Chem. 276: 23092-23096.

    Google Scholar 

  • Varadhachary, A. S., Edidin, M., Hanlon, A. M., Peter, M. E., Krammer, P. H., and Salgame, P. (2001). Phosphatidylinositol 3′-kinase blocks CD95 aggregation and caspase-8 cleavage at the death-inducing signaling complex by modulating lateral diffusion of CD95. J. Immunol. 166: 6564-6569.

    Google Scholar 

  • Whitmarsh, A. J., and Davis, R. J. (1998). Structural organization of MAP-kinase signaling modules by scaffold proteins in yeast and mammals. Trends Biochem. Sci. 23: 481-485.

    Google Scholar 

  • Xia, Z., Dickens, M., Raingeaud, J., Davis, R. J., and Greenberg, M. E. (1995). Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270: 1326-1331.

    Google Scholar 

  • Zou, W., Zeng, J., Zhuo, M., Xu, W., Sun, L., Wang, J., and Liu, X. (2002). Involvement of caspase-3 and p38 mitogen-activated protein kinase in cobalt chloride-induced apoptosis in PC12 cells. J. Neurosci. Res. 67: 837-843.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology, Yonsei University College of Medicine, Brain Korea 21 Project for Medical Science, and Institute for Immunology and Immunological Disease, Seoul, South Korea

    E. Yang, H. Kim, J. Lee, J.-S. Shin, S.-J. Kim & I.-H. Choi

  2. Department of Anatomy, College of Medicine, Pochon CHA University, Bundang, Gyunggi-do, South Korea

    H. Yoon

Authors
  1. E. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J.-S. Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S.-J. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. I.-H. Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, E., Kim, H., Lee, J. et al. Overexpression of LIM Kinase 1 Renders Resistance to Apoptosis in PC12 Cells by Inhibition of Caspase Activation. Cell Mol Neurobiol 24, 181–192 (2004). https://doi.org/10.1023/B:CEMN.0000018615.84358.33

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:CEMN.0000018615.84358.33

Search

Navigation