Skip to main content
Download PDF
  • Research Article
  • Published:

Mislocalization of CDK11/PITSLRE, a regulator of the G2/M phase of the cell cycle, in Alzheimer disease

Cellular & Molecular Biology Letters volume 16, pages 359–372 (2011)Cite this article

Abstract

Post-mitotic neurons are typically terminally differentiated and in a quiescent status. However, in Alzheimer disease (AD), many neurons display ectopic re-expression of cell cycle-related proteins. Cyclin-dependent kinase 11 (CDK11) mRNA produces a 110-kDa protein (CDK11p110) throughout the cell cycle, a 58-kDa protein (CDK11p58) that is specifically translated from an internal ribosome entry site and expressed only in the G2/M phase of the cell cycle, and a 46-kDa protein (CDK11p46) that is considered to be apoptosis specific. CDK11 is required for sister chromatid cohesion and the completion of mitosis. In this study, we found that the expression patterns of CDK11 vary such that cytoplasmic CDK11 is increased in AD cellular processes, compared to a pronounced nuclear expression pattern in most controls. We also investigated the effect of amyloid precursor protein (APP) on CDK11 expression in vitro by using M17 cells overexpressing wild-type APP and APP Swedish mutant phenotype and found increased CDK11 expression compared to empty vector. In addition, amyloid-β25–35 resulted in increased CDK11 in M17 cells. These data suggest that CDK11 may play a vital role in cell cycle re-entry in AD neurons in an APP-dependent manner, thus presenting an intriguing novel function of the APP signaling pathway in AD.

Abbreviations

Aβ:

amyloid-β

AD:

Alzheimer disease

APP:

amyloid precursor protein

CDK11:

cyclin-dependent kinase 11

CDKIs:

cyclin-dependent kinase inhibitors

IRES:

internal ribosome entry site

MT:

microtubule

References

  1. Rosenberg, R.N. The molecular and genetic basis of AD: the end of the beginning: the 2000 Wartenberg lecture. Neurology 54 (2000) 2045–2054.

    PubMed  CAS  Google Scholar 

  2. Steele, C.D. The genetics of Alzheimer disease. Nurs. Clin. North Am. 35 (2000) 687–694.

    PubMed  CAS  Google Scholar 

  3. Smith, M.A. Alzheimer disease. Int. Rev. Neurobiol. 42 (1998) 1–54.

    Article  PubMed  Google Scholar 

  4. Vincent, I., Rosado, M. and Davies, P. Mitotic mechanisms in Alzheimer’s disease? J. Cell Biol. 132 (1996) 413–425.

    Article  PubMed  CAS  Google Scholar 

  5. Vincent, I., Jicha, G., Rosado, M. and Dickson, D.W. Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer’s disease brain. J. Neurosci. 17 (1997) 3588–3598.

    PubMed  CAS  Google Scholar 

  6. McShea, A., Wahl, A.F. and Smith, M.A. Re-entry into the cell cycle: a mechanism for neurodegeneration in Alzheimer disease. Med. Hypotheses 52 (1999) 525–527.

    Article  PubMed  CAS  Google Scholar 

  7. Arendt, T., Rodel, L., Gartner, U. and Holzer, M. Expression of the cyclin-dependent kinase inhibitor p16 in Alzheimer’s disease. Neuroreport 7 (1996) 3047–3049.

    Article  PubMed  CAS  Google Scholar 

  8. McShea, A., Harris, P.L., Webster, K.R., Wahl, A.F. and Smith, M.A. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer’s disease. Am. J. Pathol. 150 (1997) 1933–1939.

    PubMed  CAS  Google Scholar 

  9. Raina, A.K., Zhu, X. and Smith, M.A. Alzheimer’s disease and the cell cycle. Acta Neurobiol. Exp. (Wars) 64 (2004) 107–112.

    Google Scholar 

  10. Zhu, X., Raina, A.K., Boux, H., Simmons, Z.L., Takeda, A. and Smith, M.A. Activation of oncogenic pathways in degenerating neurons in Alzheimer disease. Int. J. Dev. Neurosci. 18 (2000) 433–437.

    Article  PubMed  CAS  Google Scholar 

  11. Nagy, Z., Esiri, M.M., Hindley, N.J., Joachim, C., Morris, J.H., King, E.M., McDonald, B., Litchfield, S., Barnetson, L., Jobst, K.A. and Smith, A.D. Accuracy of clinical operational diagnostic criteria for Alzheimer’s disease in relation to different pathological diagnostic protocols. Dement. Geriatr. Cogn. Disord. 9 (1998) 219–226.

    Article  PubMed  CAS  Google Scholar 

  12. Lee, H.G., Casadesus, G., Zhu, X., Castellani, R.J., McShea, A., Perry, G., Petersen, R.B., Bajic, V. and Smith, M.A. Cell cycle re-entry mediated neurodegeneration and its treatment role in the pathogenesis of Alzheimer’s disease. Neurochem. Int. 54 (2009) 84–88.

    Article  PubMed  CAS  Google Scholar 

  13. Varvel, N.H., Bhaskar, K., Patil, A.R., Pimplikar, S.W., Herrup, K. and Lamb, B.T. Abeta oligomers induce neuronal cell cycle events in Alzheimer’s disease. J. Neurosci. 28 (2008) 10786–10793.

    Article  PubMed  CAS  Google Scholar 

  14. Tomiyama, T., Matsuyama, S., Iso, H., Umeda, T., Takuma, H., Ohnishi, K., Ishibashi, K., Teraoka, R., Sakama, N., Yamashita, T., Nishitsuji, K., Ito, K., Shimada, H., Lambert, M.P., Klein, W.L. and Mori, H. A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J. Neurosci. 30 (2010) 4845–4856.

    Article  PubMed  CAS  Google Scholar 

  15. Tomiyama, T., Nagata, T., Shimada, H., Teraoka, R., Fukushima, A., Kanemitsu, H., Takuma, H., Kuwano, R., Imagawa, M., Ataka, S., Wada, Y., Yoshioka, E., Nishizaki, T., Watanabe, Y. and Mori, H. A new amyloid beta variant favoring oligomerization in Alzheimer’s-type dementia. Ann. Neurol. 63 (2008) 377–387.

    Article  PubMed  CAS  Google Scholar 

  16. Lavoie, J.N., Rivard, N., L’Allemain, G. and Pouyssegur, J. A temporal and biochemical link between growth factor-activated MAP kinases, cyclin D1 induction and cell cycle entry. Prog. Cell Cycle Res. 2 (1996) 49–58.

    Article  PubMed  CAS  Google Scholar 

  17. Reed, S.I. G1/S regulatory mechanisms from yeast to man. Prog. Cell Cycle Res. 2 (1996) 15–27.

    Article  PubMed  CAS  Google Scholar 

  18. Grana, X. and Reddy, E.P. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene 11 (1995) 211–219.

    PubMed  CAS  Google Scholar 

  19. McDonald, D.R., Bamberger, M.E., Combs, C.K. and Landreth, G.E. beta-Amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes. J. Neurosci. 18 (1998) 4451–4460.

    PubMed  CAS  Google Scholar 

  20. Zhang, S., Cai, M., Zhang, S., Xu, S., Chen, S., Chen, X., Chen, C. and Gu, J. Interaction of p58(PITSLRE), a G2/M-specific protein kinase, with cyclin D3. J. Biol. Chem. 277 (2002) 35314–35322.

    Article  PubMed  CAS  Google Scholar 

  21. Li, Z., Wang, H., Zong, H., Sun, Q., Kong, X., Jiang, J. and Gu, J. Downregulation of beta1,4-galactosyltransferase 1 inhibits CDK11(p58)-mediated apoptosis induced by cycloheximide. Biochem. Biophys. Res. Commun. 327 (2005) 628–636.

    Article  PubMed  CAS  Google Scholar 

  22. Xiang, J., Lahti, J.M., Grenet, J., Easton, J. and Kidd, V.J. Molecular cloning and expression of alternatively spliced PITSLRE protein kinase isoforms. J. Biol. Chem. 269 (1994) 15786–15794.

    PubMed  CAS  Google Scholar 

  23. Gururajan, R., Lahti, J.M., Grenet, J., Easton, J., Gruber, I., Ambros, P.F. and Kidd, V.J. Duplication of a genomic region containing the Cdc2L1–2 and MMP21–22 genes on human chromosome 1p36.3 and their linkage to D1Z2. Genome Res. 8 (1998) 929–939.

    PubMed  CAS  Google Scholar 

  24. Shi, J. and Nelson, M.A. The cyclin-dependent kinase 11 interacts with NOT2. Biochem. Biophys. Res. Commun. 334 (2005) 1310–1316.

    Article  PubMed  CAS  Google Scholar 

  25. Loyer, P., Trembley, J.H., Katona, R., Kidd, V.J. and Lahti, J.M. Role of CDK/cyclin complexes in transcription and RNA splicing. Cell. Signal. 17 (2005) 1033–1051.

    Article  PubMed  CAS  Google Scholar 

  26. Yokoyama, H., Gruss, O.J., Rybina, S., Caudron, M., Schelder, M., Wilm, M., Mattaj, I.W. and Karsenti, E. Cdk11 is a RanGTP-dependent microtubule stabilization factor that regulates spindle assembly rate. J. Cell Biol. 180 (2008) 867–875.

    Article  PubMed  CAS  Google Scholar 

  27. Petretti, C., Savoian, M., Montembault, E., Glover, D.M., Prigent, C. and Giet, R. The PITSLRE/CDK11p58 protein kinase promotes centrosome maturation and bipolar spindle formation. EMBO Rep. 7 (2006) 418–424.

    PubMed  CAS  Google Scholar 

  28. Lahti, J.M., Xiang, J., Heath, L.S., Campana, D. and Kidd, V.J. PITSLRE protein kinase activity is associated with apoptosis. Mol. Cell. Biol. 15 (1995) 1–11.

    PubMed  CAS  Google Scholar 

  29. Hu, D., Valentine, M., Kidd, V.J. and Lahti, J.M. CDK11(p58) is required for the maintenance of sister chromatid cohesion. J. Cell Sci. 120 (2007) 2424–2434.

    Article  PubMed  CAS  Google Scholar 

  30. Bunnell, B.A., Heath, L.S., Adams, D.E., Lahti, J.M. and Kidd, V.J. Increased expression of a 58-kDa protein kinase leads to changes in the CHO cell cycle. Proc. Natl. Acad. Sci. U. S. A. 87 (1990) 7467–7471.

    Article  PubMed  CAS  Google Scholar 

  31. Zong, H., Chi, Y., Wang, Y., Yang, Y., Zhang, L., Chen, H., Jiang, J., Li, Z., Hong, Y., Wang, H., Yun, X. and Gu, J. Cyclin D3/CDK11p58 complex is involved in the repression of androgen receptor. Mol. Cell. Biol. 27 (2007) 7125–7142.

    Article  PubMed  CAS  Google Scholar 

  32. Hu, D., Mayeda, A., Trembley, J.H., Lahti, J.M. and Kidd, V.J. CDK11 complexes promote pre-mRNA splicing. J. Biol. Chem. 278 (2003) 8623–8629.

    Article  PubMed  CAS  Google Scholar 

  33. Chen, H.H., Wang, Y.C. and Fann, M.J. Identification and characterization of the CDK12/cyclin L1 complex involved in alternative splicing regulation. Mol. Cell. Biol. 26 (2006) 2736–2745.

    Article  PubMed  CAS  Google Scholar 

  34. Trembley, J.H., Hu, D., Hsu, L.C., Yeung, C.Y., Slaughter, C., Lahti, J.M. and Kidd, V.J. PITSLRE p110 protein kinases associate with transcription complexes and affect their activity. J. Biol. Chem. 277 (2002) 2589–2596.

    Article  PubMed  CAS  Google Scholar 

  35. Wendt, K.S., Yoshida, K., Itoh, T., Bando, M., Koch, B., Schirghuber, E., Tsutsumi, S., Nagae, G., Ishihara, K., Mishiro, T., Yahata, K., Imamoto, F., Aburatani, H., Nakao, M., Imamoto, N., Maeshima, K., Shirahige, K. and Peters, J.M. Cohesin mediates transcriptional insulation by CCCTC-binding factor. Nature 451 (2008) 796–801.

    Article  PubMed  CAS  Google Scholar 

  36. Spremo-Potparevic, B., Zivkovic, L., Djelic, N. and Bajic, V. Analysis of premature centromere division (PCD) of the X chromosome in Alzheimer patients through the cell cycle. Exp. Gerontol. 39 (2004) 849–854.

    Article  PubMed  CAS  Google Scholar 

  37. Zivkovic, L., Spremo-Potparevic, B., Djelic, N. and Bajic, V. Analysis of premature centromere division (PCD) of the chromosome 18 in peripheral blood lymphocytes in Alzheimer disease patients. Mech. Ageing Dev. 127 (2006) 892–896.

    Article  PubMed  CAS  Google Scholar 

  38. Bajic, V.P., Spremo-Potparevic, B., Zivkovic, L., Djelic, N. and Smith, M.A. Is the time dimension of the cell cycle re-entry in AD regulated by centromere cohesion dynamics? Biosci. Hypotheses 1 (2008) 156–161.

    Article  PubMed  Google Scholar 

  39. Migliore, L., Testa, A., Scarpato, R., Pavese, N., Petrozzi, L. and Bonuccelli, U. Spontaneous and induced aneuploidy in peripheral blood lymphocytes of patients with Alzheimer’s disease. Hum. Genet. 101 (1997) 299–305.

    Article  PubMed  CAS  Google Scholar 

  40. Sternberger, L.A. Immunocytochemistry, Wiley, New York, 1986.

    Google Scholar 

  41. Wang, X., Su, B., Siedlak, S.L., Moreira, P.I., Fujioka, H., Wang, Y., Casadesus, G. and Zhu, X. Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 19318–19323.

    Article  PubMed  CAS  Google Scholar 

  42. Su, B., Wang, X., Drew, K.L., Perry, G., Smith, M.A. and Zhu, X. Physiological regulation of tau phosphorylation during hibernation. J. Neurochem. 105 (2008) 2098–2108.

    Article  PubMed  CAS  Google Scholar 

  43. Wang, X., Su, B., Fujioka, H. and Zhu, X. Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer’s disease patients. Am. J. Pathol. 173 (2008) 470–482.

    Article  PubMed  CAS  Google Scholar 

  44. Zhu, X., McShea, A., Harris, P.L., Raina, A.K., Castellani, R.J., Funk, J.O., Shah, S., Atwood, C., Bowen, R., Bowser, R., Morelli, L., Perry, G. and Smith, M.A. Elevated expression of a regulator of the G2/M phase of the cell cycle, neuronal CIP-1-associated regulator of cyclin B, in Alzheimer’s disease. J. Neurosci. Res. 75 (2004) 698–703.

    Article  PubMed  CAS  Google Scholar 

  45. Harris, P.L., Zhu, X., Pamies, C., Rottkamp, C.A., Ghanbari, H.A., McShea, A., Feng, Y., Ferris, D.K. and Smith, M.A. Neuronal polo-like kinase in Alzheimer disease indicates cell cycle changes. Neurobiol. Aging 21 (2000) 837–841.

    Article  PubMed  CAS  Google Scholar 

  46. Previll, L.A., Crosby, M.E., Castellani, R.J., Bowser, R., Perry, G., Smith, M.A. and Zhu, X. Increased expression of p130 in Alzheimer disease. Neurochem. Res. 32 (2007) 639–644.

    Article  PubMed  CAS  Google Scholar 

  47. Ogawa, O., Zhu, X., Lee, H.G., Raina, A., Obrenovich, M.E., Bowser, R., Ghanbari, H.A., Castellani, R.J., Perry, G. and Smith, M.A. Ectopic localization of phosphorylated histone H3 in Alzheimer’s disease: a mitotic catastrophe? Acta Neuropathol. (Berl). 105 (2003) 524–528.

    CAS  Google Scholar 

  48. Bonda, D.J., Bajic, V.P., Spremo-Potparevic, B., Casadesus, G., Zhu, X., Smith, M.A. and Lee, H.G. Cell Cycle Aberrations and Neurodegeneration: A Review. Neuropathol. Appl. Neurobiol. 36 (2010) 157–163.

    Article  PubMed  CAS  Google Scholar 

  49. Zhu, X., Raina, A.K., Lee, H.G., Chao, M., Nunomura, A., Tabaton, M., Petersen, R.B., Perry, G. and Smith, M.A. Oxidative stress and neuronal adaptation in Alzheimer disease: the role of SAPK pathways. Antioxid. Redox Signal. 5 (2003) 571–576.

    Article  PubMed  CAS  Google Scholar 

  50. Mosch, B., Morawski, M., Mittag, A., Lenz, D., Tarnok, A. and Arendt, T. Aneuploidy and DNA replication in the normal human brain and Alzheimer’s disease. J. Neurosci. 27 (2007) 6859–6867.

    Article  PubMed  CAS  Google Scholar 

  51. Yang, Y., Geldmacher, D.S. and Herrup, K. DNA replication precedes neuronal cell death in Alzheimer’s disease. J. Neurosci. 21 (2001) 2661–2668.

    PubMed  CAS  Google Scholar 

  52. Zhu, X., Siedlak, S.L., Wang, Y., Perry, G., Castellani, R.J., Cohen, M.L. and Smith, M.A. Neuronal binucleation in Alzheimer disease hippocampus. Neuropathol. Appl. Neurobiol. 34 (2008) 457–465.

    Article  PubMed  CAS  Google Scholar 

  53. Spremo-Potparevic, B., Zivkovic, L., Djelic, N., Plecas-Solarovic, B., Smith, M.A. and Bajic, V. Premature centromere division of the X chromosome in neurons in Alzheimer’s disease. J. Neurochem. 106 (2008) 2218–2223.

    Article  PubMed  CAS  Google Scholar 

  54. Cash, A.D., Aliev, G., Siedlak, S.L., Nunomura, A., Fujioka, H., Zhu, X., Raina, A.K., Vinters, H.V., Tabaton, M., Johnson, A.B., Paula-Barbosa, M., Avila, J., Jones, P.K., Castellani, R.J., Smith, M.A. and Perry, G. Microtubule reduction in Alzheimer’s disease and aging is independent of tau filament formation. Am. J. Pathol. 162 (2003) 1623–1627.

    Article  PubMed  CAS  Google Scholar 

  55. Lee, H.G., Ueda, M., Miyamoto, Y., Yoneda, Y., Perry, G., Smith, M.A. and Zhu, X. Aberrant localization of importin alpha1 in hippocampal neurons in Alzheimer disease. Brain Res. 1124 (2006) 1–4.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Biomedical Research, Galenika a.d., 11000, Belgrade, Serbia

    Vladan P. Bajić

  2. Department of Pathology, Case Western Reserve University, Cleveland, Ohio, 44106, USA

    Bo Su, Hyoung-Gon Lee, Wataru Kudo, Sandra L. Siedlak, Avneet K. Singh, Lara M. Fahmy, Xinglong Wang, Mark A. Smith & Xiongwei Zhu

  3. Institute of Physiology, Department of Biology and Human Genetics, Faculty of Pharmacy, University of Belgrade, 11000, Belgrade, Serbia

    Lada Živković & Biljana Spremo-Potparević

  4. Department of Biology, Faculty of Veterinary Medicine, University of Belgrade, 11000, Belgrade, Serbia

    Ninoslav Djelic

  5. Department of Endocrinology and Molecular Biology, Institute of Nuclear Sciences “Vinca”, Belgrade, Serbia

    Zorana Milicevic

Authors
  1. Vladan P. Bajić
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bo Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hyoung-Gon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wataru Kudo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sandra L. Siedlak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lada Živković
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Biljana Spremo-Potparević
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ninoslav Djelic
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zorana Milicevic
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Avneet K. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lara M. Fahmy
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xinglong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Mark A. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xiongwei Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Vladan P. Bajić or Xiongwei Zhu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bajić, V.P., Su, B., Lee, HG. et al. Mislocalization of CDK11/PITSLRE, a regulator of the G2/M phase of the cell cycle, in Alzheimer disease. Cell Mol Biol Lett 16, 359–372 (2011). https://doi.org/10.2478/s11658-011-0011-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2478/s11658-011-0011-2

Key words

Cellular & Molecular Biology Letters

ISSN: 1689-1392

Contact us