Skip to main content

Advertisement

SpringerLink
Log in

Colostrinin-Driven Neurite Outgrowth Requires p53 Activation in PC12 Cells

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

Summary

1. Colostrinin (CLN) induces maturation and differentiation of murine thymocytes, promotes proliferation of peripheral blood leukocytes, induces immunomodulator cytokines, and ameliorates oxidative stress-mediated activation of c-Jun NH2-terminal kinases.

2. Here we report that upon treatment with CLN, medullary pheochromocytoma (PC12) cells ceased to proliferate and extend neurites.

3. The arrest of CLN-treated PC12 cells in the G1 phase of the cell cycle was due to an increase in the phosphorylation of p53 at serine15 (p53ser15) and expression of p21WAF1. PC12 cells treated with inhibitory oligonucleotides to p53 lacked p53ser15 and p21WAF1 expression, and did not show morphological changes after CLN exposure. Transfection with inhibitory oligonucleotides to p21WAF1 had no effect on p53 activation; however, cells failed to arrest or extend neurites. An oligonucleotide inhibiting luciferase expression had no effect on CLN-mediated p53 activation, p21WAF1 expression, growth arrest, or neurite outgrowth.

4. We conclude that CLN induces delicate cassettes of signaling pathways common to cell proliferation and differentiation, and mediates activities that are similar to those of hormones and neurotrophins, leading to neurite outgrowth.

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

  • Aloni-Grinstein, R., Zan-Bar, I., Alboum, I., Goldfinger, N., and Rotter, V. (1993). Wild type p53 functions as a control protein in the differentiation pathway of the B-cell lineage. Oncogene 8:3297–3305.

    CAS  PubMed  Google Scholar 

  • Armstrong, J. F., Kaufman, M. H., Harrison, D. J., and Clarke, A. R. (1995). High-frequency developmental abnormalities in p53-deficient mice. Curr. Biol. 5:931–936.

    Article  CAS  PubMed  Google Scholar 

  • Benowitz, L. I., and Routtenberg, A. (1997). GAP-43: An intrinsic determinant of neuronal development and plasticity. Trends Neurosci. 20:84–91.

    Article  CAS  PubMed  Google Scholar 

  • Bilikiewicz, A., and Gaus, W. (2004). Colostrinin (a naturally occurring, proline-rich, polypeptide mixture) in the treatment of Alzheimer's disease. J. Alzheimers Dis. 6:17–26.

    CAS  PubMed  Google Scholar 

  • Boldogh, I., Hughes, T. K., Georgiades, J. A., and Stanton, G. J. (2001). Antioxidant effect of colostrinin and its component peptides. Psychogeriat. Annu. 4:57–65.

    Google Scholar 

  • Boldogh, I., Liebenthal, D., Hughes, T. K., Juelich, T. L., Georgiades, J. A., Kruzel, M. L., and Stanton, G. J. (2003a). Modulation of 4HNE-mediated signaling by proline-rich peptides from ovine colostrum. J. Mol. Neurosci. 20:125–134.

    Article  CAS  Google Scholar 

  • Boldogh, I., Milligan, D., Lee, M. S., Bassett, H., Lloyd, R. S., and McCullough, A. K. (2001). hMYH cell cycle-dependent expression, subcellular localization and association with replication foci: Evidence suggesting replication-coupled repair of adenine:8-oxoguanine mispairs. Nucleic Acids Res. 29:2802–2809.

    Article  CAS  PubMed  Google Scholar 

  • Boldogh, I., Roy, G., Lee, M. S., Bacsi, A., Hazra, T. K., Bhakat, K. K., Das, G. C., and Mitra, S. (2003b). Reduced DNA double strand breaks in chlorambucil resistant cells are related to high DNA-PKcs activity and low oxidative stress. Toxicology 193:137–152.

    Article  CAS  Google Scholar 

  • Bresnahan, W. A., Boldogh, I., Chi, P., Thompson, E. A., and Albrecht, T. (1997). Inhibition of cellular Cdk2 activity blocks human cytomegalovirus replication. Virology 231:239–247.

    Article  CAS  PubMed  Google Scholar 

  • Carter, A. N., and Downes, C. P. (1992). Phosphatidylinositol 3-kinase is activated by nerve growth factor and epidermal growth factor in PC12 cells. J. Biol. Chem. 267:14563–14567.

    CAS  PubMed  Google Scholar 

  • Chen, R. W., Saunders, P. A., Wei, H., Li, Z., Seth, P., and Chuang, D. M. (1999). Involvement of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and p53 in neuronal apoptosis: Evidence that GAPDH is upregulated by p53. J. Neurosci. 19:9654–9662.

    CAS  PubMed  Google Scholar 

  • Costello, B., Meymandi, A., and Freeman, J. A. (1990). Factors influencing GAP-43 gene expression in PC12 pheochromocytoma cells. J. Neurosci. 10:1398–1406.

    CAS  PubMed  Google Scholar 

  • D'Arcangelo, G., and Halegoua, S. (1993). A branched signaling pathway for nerve growth factor is revealed by Src-, Ras-, and Raf-mediated gene inductions. Mol. Cell. Biol. 13:3146–3155.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Elbashir, S. M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K., and Tuschl, T. (2001). Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498.

    Article  CAS  PubMed  Google Scholar 

  • el-Deiry, W. S., Harper, J. W., O'Connor, P. M., Velculescu, V. E., Canman, C. E., Jackman, J., Pietenpol, J. A., Burrell, M., Hill, D. E., Wang, Y., Winman, K. G., Mercer, F., W., Kastan,M. B., Kohn, K. W., Elledge, S. J., Kinzler, K. W., and Vogelstein, B. (1994). WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 54:1169–1174.

    CAS  PubMed  Google Scholar 

  • Goslin, K., and Banker, G. (1990). Rapid changes in the distribution of GAP-43 correlate with the expression of neuronal polarity during normal development and under experimental conditions. J. Cell. Biol. 110:1319–1331.

    Article  CAS  PubMed  Google Scholar 

  • Greene, L. A., and Tischler, A. S. (1976). Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc. Natl. Acad. Sci. USA 73:2424–2428.

    Article  CAS  PubMed  Google Scholar 

  • Halevy, O., Novitch, B. G., Spicer, D. B., Skapek, S. X., Rhee, J., Hannon, G. J., Beach, D., and Lassar, A. B. (1995). Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science 267:1018–1021.

    Article  CAS  PubMed  Google Scholar 

  • Harris, S. L., and Levine, A. J. (2005). The p53 pathway: Positive and negative feedback loops. Oncogene 24:2899–2908.

    Article  CAS  PubMed  Google Scholar 

  • Hollstein, M., Sidransky, D., Vogelstein, B., and Harris, C. C. (1991). p53 mutations in human cancers. Science 253:49–53.

    Article  CAS  PubMed  Google Scholar 

  • Hosang, M., and Shooter, E. M. (1987). The internalization of nerve growth factor by high-affinity receptors on pheochromocytoma PC12 cells. EMBO J. 6:1197–1202.

    CAS  PubMed  Google Scholar 

  • Hughes, A. L., Gollapudi, L., Sladek, T. L., and Neet, K. E. (2000). Mediation of nerve growth factor-driven cell cycle arrest in PC12 cells by p53. Simultaneous differentiation and proliferation subsequent to p53 functional inactivation. J. Biol. Chem. 275:37829–37837.

    Article  CAS  PubMed  Google Scholar 

  • Janusz, M., and Lisowski, J. (1993). Proline-rich polypeptide (PRP)—An immunomodulatory peptide from ovine colostrum. Arch. Immunol. Ther. Exp. (Warsz) 41:275–279.

    CAS  Google Scholar 

  • Janusz, M., Lisowski, J., and Franek, F. (1974). Isolation and characterization of a proline-rich polypeptide from ovine colostrum. FEBS Lett. 49:276–279.

    Article  CAS  PubMed  Google Scholar 

  • Janusz, M., Staroscik, K., Zimecki, M., Wieczorek, Z., and Lisowski, J. (1981). Chemical and physical characterization of a proline-rich polypeptide from sheep colostrum. Biochem. J. 199:9–15.

    CAS  PubMed  Google Scholar 

  • Jap Tjoen San, E. R., Schmidt-Michels, M. H., Spruijt, B. M., Oestreicher, A. B., Schotman, P., and Gispen, W. H. (1991). Quantitation of the growth-associated protein B-50/GAP-43 and neurite outgrowth in PC12 cells. J. Neurosci. Res. 29:149–154.

    Article  CAS  PubMed  Google Scholar 

  • Klesse, L. J., and Parada, L. F. (1999). Trks: Signal transduction and intracellular pathways. Microsc. Res. Tech. 45:210–216.

    Article  CAS  PubMed  Google Scholar 

  • Kruzel, M. L., Janusz, M., Lisowski, J., Fischleigh, R. V., and Georgiades, J. A. (2001). Towards an understanding of biological role of colostrinin peptides. J. Mol. Neurosci. 17:379–389.

    Article  CAS  PubMed  Google Scholar 

  • Kruzel, M. L., Polanowski, A., Wilusz, T., Sokolowska, A., Pacewicz, M., Bednarz, R., and Georgiades, J. A. (2004). The alcohol-induced conformational changes in casein micelles: A new challenge for the purification of colostrinin. Protein J. 23:127–133.

    Article  CAS  PubMed  Google Scholar 

  • Leszek, J., Inglot, A. D., Janusz, M., Lisowski, J., Krukowska, K., and Georgiades, J. A. (1999). Colostrinin: A proline-rich polypeptide (PRP) complex isolated from ovine colostrum for treatment of Alzheimer's disease. A double-blind, placebo-controlled study. Arch. Immunol. Ther. Exp. (Warsz) 47:377–385.

    CAS  Google Scholar 

  • Levi, A., Biocca, S., Cattaneo, A., and Calissano, P. (1988). The mode of action of nerve growth factor in PC12 cells. Mol. Neurobiol. 2:201–226.

    Article  CAS  PubMed  Google Scholar 

  • Levine, A. J. (1997). p53, the cellular gatekeeper for growth and division. Cell 88:323–331.

    Article  CAS  PubMed  Google Scholar 

  • Liebermann, D. A., Hoffman, B., and Steinman, R. A. (1995). Molecular controls of growth arrest and apoptosis: p53-dependent and independent pathways. Oncogene 11:199–210.

    CAS  PubMed  Google Scholar 

  • Lin, D., Shields, M. T., Ullrich, S. J., Appella, E., and Mercer, W. E. (1992). Growth arrest induced by wild-type p53 protein blocks cells prior to or near the restriction point in late G1 phase. Proc. Natl. Acad. Sci. USA 89:9210–9214.

    Article  CAS  PubMed  Google Scholar 

  • Marek, L., Levresse, V., Amura, C., Zentrich, E., Van Putten, V., Nemenoff, R. A., and Heasley, L. E. (2004). Multiple signaling conduits regulate global differentiation-specific gene expression in PC12 cells. J. Cell. Physiol. 201:459–469.

    Article  CAS  PubMed  Google Scholar 

  • Mohiuddin, L., Fernandez, K., Tomlinson, D. R., and Fernyhough, P. (1995). Nerve growth factor and neurotrophin-3 enhance neurite outgrowth and up-regulate the levels of messenger RNA for growth-associated protein GAP-43 and T alpha 1 alpha-tubulin in cultured adult rat sensory neurones. Neurosci. Lett. 185:20–23.

    Article  CAS  PubMed  Google Scholar 

  • O'Driscoll, C. M., and Gorman, A. M. (2005). Hypoxia induces neurite outgrowth in PC12 cells that is mediated through adenosine A2A receptors. Neuroscience 131:321–329.

    Article  PubMed  Google Scholar 

  • Ohmichi, M., Decker, S. J., Pang, L., and Saltiel, A. R. (1992). Inhibition of the cellular actions of nerve growth factor by staurosporine and K252A results from the attenuation of the activity of the trk tyrosine kinase. Biochemistry 31:4034–4039.

    Article  CAS  PubMed  Google Scholar 

  • Poluha, W., Schonhoff, C. M., Harrington, K. S., Lachyankar, M. B., Crosbie, N. E., Bulseco, D. A., and Ross, A. H. (1997). A novel, nerve growth factor-activated pathway involving nitric oxide, p53, and p21WAF1 regulates neuronal differentiation of PC12 cells. J. Biol. Chem. 272:24002–24007.

    Article  CAS  PubMed  Google Scholar 

  • Przyborski, S. A., and Cambray-Deakin, M. A. (1994). Developmental changes in GAP-43 expression in primary cultures of rat cerebellar granule cells. Brain Res. Mol. Brain Res. 25:273–285.

    Article  CAS  PubMed  Google Scholar 

  • Ramakers, G. M., De Graan, P. N., Urban, I. J., Kraay, D., Tang, T., Pasinelli, P., Oestreicher, A. B., and Gispen, W. H. (1995). Temporal differences in the phosphorylation state of pre- and postsynaptic protein kinase C substrates B-50/GAP-43 and neurogranin during long-term potentiation. J. Biol. Chem. 270:13892–13898.

    Article  CAS  PubMed  Google Scholar 

  • Riese, U., Ziegler, E., and Hamburger, M. (2004). Militarinone A induces differentiation in PC12 cells via MAP and Akt kinase signal transduction pathways. FEBS Lett. 577:455–459.

    Article  CAS  PubMed  Google Scholar 

  • Sah, V. P., Attardi, L. D., Mulligan, G. J., Williams, B. O., Bronson, R. T., and Jacks, T. (1995). A subset of p53-deficient embryos exhibit exencephaly. Nat. Genet. 10:175–180.

    Article  CAS  PubMed  Google Scholar 

  • Schwamborn, J. C., Fiore, R., Bagnard, D., Kappler, J., Kaltschmidt, C., and Puschel, A. W. (2004). Semaphorin 3A stimulates neurite extension and regulates gene expression in PC12 cells. J. Biol. Chem. 279:30923–30926.

    Article  CAS  PubMed  Google Scholar 

  • Shaulsky, G., Goldfinger, N., Peled, A., and Rotter, V. (1991). Involvement of wild-type p53 protein in the cell cycle requires nuclear localization. Cell Growth Differ. 2:661–667.

    CAS  PubMed  Google Scholar 

  • Skene, J. H., and Virag, I. (1989). Posttranslational membrane attachment and dynamic fatty acylation of a neuronal growth cone protein, GAP-43. J. Cell. Biol. 108:613–624.

    Article  CAS  PubMed  Google Scholar 

  • Stanton, G., Boldogh, I., Georgiades, J. A., and Hughes, T. K. (2001). Induction of cell prolipheration and cytokines by colostrinin and component proline-rich peptides in human peripheral blood leukocytes. Psychogeriat. Annu. 4:67–75.

    Google Scholar 

  • Sumantran, V. N., and Feldman, E. L. (1993). Insulin-like growth factor I regulates c-myc and GAP-43 messenger ribonucleic acid expression in SH-SY5Y human neuroblastoma cells. Endocrinology 132:2017–2023.

    Article  CAS  PubMed  Google Scholar 

  • Szczesny, B., Bhakat, K. K., Mitra, S., and Boldogh, I. (2004). Age-dependent modulation of DNA repair enzymes by covalent modification and subcellular distribution. Mech. Ageing Dev. 125:755–765.

    Article  CAS  PubMed  Google Scholar 

  • Szeberenyi, J. (1996). Gene activation pathways of nerve growth factor signaling: A minireview. Neurobiology (Bp) 4:1–11.

    CAS  Google Scholar 

  • Tsukada, T., Tomooka, Y., Takai, S., Ueda, Y., Nishikawa, S., Yagi, T., Tokunaga, T., Takeda, N., Suda, Y., Abe, S., Matsuo, I., Ikawa, Y., and Aizawa, S. (1993). Enhanced proliferative potential in culture of cells from p53-deficient mice. Oncogene 8:3313–3322.

    CAS  PubMed  Google Scholar 

  • Vaskovsky, A., Lupowitz, Z., Erlich, S., and Pinkas-Kramarski, R. (2000). ErbB-4 activation promotes neurite outgrowth in PC12 cells. J. Neurochem. 74:979–987.

    Article  CAS  PubMed  Google Scholar 

  • Vaudry, D., Stork, P. J., Lazarovici, P., and Eiden, L. E. (2002). Signaling pathways for PC12 cell differentiation: Making the right connections. Science 296:1648–1649.

    Article  CAS  PubMed  Google Scholar 

  • Weiss, R. H., and Randour, C. J. (2000). The permissive effect of p21 (Waf1/Cip1) on DNA synthesis is dependent on cell type: Effect is absent in p53-inactive cells. Cell. Signal 12:413–418.

    Article  CAS  PubMed  Google Scholar 

  • Wood, K. W., Sarnecki, C., Roberts, T. M., and Blenis, J. (1992). ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. Cell 68:1041–1050.

    Article  CAS  PubMed  Google Scholar 

  • Wu, Y. Y., and Bradshaw, R. A. (1996). Synergistic induction of neurite outgrowth by nerve growth factor or epidermal growth factor and interleukin-6 in PC12 cells. J. Biol. Chem. 271:13033–13039.

    Article  CAS  PubMed  Google Scholar 

  • Xiao, J., and Liu, Y. (2003). Differential roles of ERK and JNK in early and late stages of neuritogenesis: a study in a novel PC12 model system. J. Neurochem. 86:1516–1523.

    Article  CAS  PubMed  Google Scholar 

  • Yoo, Y. E., Hong, J. H., Hur, K. C., Oh, E. S., and Chung, J. M. (2004). Iron enhances NGF-induced neurite outgrowth in PC12 cells. Mol. Cells 17:340–346.

    CAS  PubMed  Google Scholar 

  • Zimecki, M., Lisowski, J., Hraba, T., Wieczorek, Z., Janusz, M., and Staroscik, K. (1984). The effect of a proline-rich polypeptide (PRP) on the humoral immune response. I. Distinct effect of PRP on the T cell properties of mouse glass-nonadherent (NAT) and glass-adherent (GAT) thymocytes in thymectomized mice. Arch. Immunol. Ther. Exp. (Warsz) 32:191–196.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, Texas

    Attila Bacsi, G. John Stanton, Thomas K. Hughes & Istvan Boldogh

  2. Department of Integrative Biology, Pharmacology and Physiology, UT-Houston Medical School, Houston, Texas

    Marian Kruze

  3. ReGen Therapeutics, Plc, London, England

    Marian Kruze

  4. Present address: Institute of Immunology, University of Debrecen, Debrecen, H-4012, Hungary

    Attila Bacsi

  5. Department of Microbiology and Immunology, University of Texas Medical Branch, 3.170 Medical Research Building, 301 University Blvd, Galveston, Texas, 77555

    Istvan Boldogh

Authors
  1. Attila Bacsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. John Stanton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas K. Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marian Kruze
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Istvan Boldogh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Istvan Boldogh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bacsi, A., Stanton, G.J., Hughes, T.K. et al. Colostrinin-Driven Neurite Outgrowth Requires p53 Activation in PC12 Cells. Cell Mol Neurobiol 25, 1123–1139 (2005). https://doi.org/10.1007/s10571-005-8222-6

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-005-8222-6

Key Words

Search

Navigation