|
|
|
|
|
|
||
|
|
||||
|
|
||||
|
||||
Tumor Biology |
Cross Cancer Institute, Edmonton, Alberta T6G 1Z2 (A.C., S.U., E.Y., G.B., J.A.-T.); and the Departments of Laboratory Medicine and Pathology (C.H.) and Oncology (A.C., E.Y., J.A.-T.), University of Alberta, Edmonton, Alberta, Canada T6G 2E1
3 Address correspondence and reprint requests to Joan Allalunis-Turner, Experimental Oncology, Cross Cancer Institute, 11560 University Ave., Edmonton, AB, Canada T6G 1Z2.
Abstract
Cyclin-dependent kinase 5 (Cdk5), a member of the cyclin-dependent kinase family, is expressed predominately in mature neurons and is implicated in neurite extension, neuronal migration, and neuronal differentiation. Cdk5 protein expression also has been associated with apoptosis in a number of nonneuronal model systems. In normal brain, substrates for Cdk5 include neurofilament and tau proteins. Because human tumors of glial origin can express neuronal proteins, we examined whether Cdk5 and its activator protein, P35, are present in early passage human glioblastoma multiforme (GBM) cells lines and primary tumor specimens. Here we report the expression of Cdk5 and an "active" proteolytic form of P35 in human GBM cells and demonstrate kinase activity of the holoenzyme. We also show that Cdk5 kinase activity and expression of its activator protein, P35, is increased in the human GBM cell line M059J after exposure to ionizing radiation and that P35 is localized within M059J cells undergoing apoptosis. These results suggest a possible role for Cdk5 in mediating apoptosis in human GBM cells.
References
Abaza, M.S.J., Shaban, F., Narayan, R.K., and Atassi, M.Z. (1998) Human glioma associated intermediate filament proteins: Over-expression, co-localization and cross-reactivity. Anticancer Res. 18,1333 -1340.[ISI][Medline]
Ahuja, H.S., Zhu, Y., and Zakeri, Z. (1997) Association of cyclin-dependent kinase 5 and its activator p35 with apoptotic cell death. Dev. Genet. 21,258 -267.[CrossRef][ISI][Medline]
Allalunis-Turner, M.J., Barron, G.M., Day, R.S., III, Fulton, D.S., and Urtasun, R.C. (1992) Radiosensitivity testing of human primary brain tumor specimens. Int. J. Radiat. Oncol. Biol. Phys. 23,339 -343.[ISI][Medline]
Allalunis-Turner, M.J., Barron, G.M., Day, R.S., III, Dobler, K.D., and Mirzayans, R. (1993) Isolation of two cell lines from a human malignant glioma specimen differing in sensitivity to radiation and chemotherapeutic drugs. Radiat. Res. 134,349 -354.[ISI][Medline]
Beaudette, K.N., Lew, J., and Wang, J.H. (1993)
Substrate specificity characterization of a cdc2-like protein kinase purified
from bovine brain. J. Biol. Chem.
268,20825
-20830.
Bodey, B., Cosgrove, M., Gonzalez-Gomez, I., Siegel, S.E., Martin, S.E., and Gilles, F.H. (1991) Co-expression of four intermediate filament subclasses in childhood glial neoplasms. Mod. Pathol. 4,742 -749.[ISI][Medline]
Brion, J. P., and Couck, A.M. (1995) Cortical and brainstem-type Lewy bodies are immunoreactive for the cyclin-dependent kinase 5. Am. J. Pathol. 147,1465 -1476.[Abstract]
Brown, N.R., Noble, M.E., Endicott, J.A., Garman, E.F., Wakatsuki, S., Mitchell, E., Rasmussen, B., Hunt, T., and Johnson, L.N. (1995) The crystal structure of cyclin A. Structure 3,1235 -1247.[Medline]
Cattaneo, E., and McKay, R. (1990) Proliferation and differentiation of neuronal stem cells by nerve growth factor. Nature 347,762 -765.[CrossRef][Medline]
Chen, F., Roa, J., and Studzinski, G.P. (2000) Specific association of increased cyclin-dependent kinase 5 expression with monocytic lineage of differentiation of human leukemia HL60 cells. J. Leukoc. Biol. 67,559 -566.[Abstract]
Delalle, I., Bhide, P.G., Caviness, V.S., Jr., and Tsai, L.H. (1997) Temporal and spatial patterns of expression of p35, a regulatory subunit of cyclin-dependent kinase 5, in the nervous system of the mouse. J. Neurocytol. 26,283 -296.[CrossRef][ISI][Medline]
Gao, C.Y., Zakeri, Z., Zhu, Y., He, H., and Zelenka, P.S. (1997) Expression of Cdk5, p35, and Cdk5-associated kinase activity in the developing rat lens. Dev. Genet. 20,267 -275.[CrossRef][ISI][Medline]
Guidato, S., McLoughlin, D.M., Grierson, A.J., and Miller, C.C.J. (1998) Cyclin D2 interacts with cdk-5 and modulates cellular cdk-5/p35 activity. J. Neurochem. 70,335 -340.[ISI][Medline]
Hayashi, T., Warita, H., Abe, K., and Itoyama, Y. (1999) Expression of cyclin-dependent kinase 5 and its activator p35 in rat brain after middle cerebral artery occlusion. Neurosci. Lett. 265,37 -40.[CrossRef][ISI][Medline]
Hellmich, M.R., Pant, H.C., Wada, E., and Battey, J.F.
(1992) Neuronal cdc2-like kinase: A cdc2-related protein kinase
with predominately neuronal expression. Proc. Natl. Acad. Sci.
U.S.A. 89,10867
-10871.
Henchcliffe, C., and Burke, R.E. (1997) Increased expression of cyclin-dependent kinase 5 in induced apoptotic neuron death in rat substantia nigra. Neurosci. Lett. 230, 41-44.[CrossRef][ISI][Medline]
Ino, H., and Chiba, T. (1996) Intracellular localization of cyclin-dependent kinase 5 (CDK5) in mouse neuron: CDK5 is located in both nucleus and cytoplasm. Brain Res. 732,179 -185.[CrossRef][ISI][Medline]
Ino, H., Ishizuka, T., Chiba, T., and Tatibana, M. (1994) Expression of CDK5 (PSSALRE kinase), a neural cdc2-related protein kinase, in the mature and developing mouse central and peripheral nervous systems. Brain Res. 661,196 -206.[CrossRef][ISI][Medline]
Kato, G., and Maeda, S. (1999) Neuron-specific Cdk5
kinase is responsible for mitosis-independent phosphorylation of c-Src at
Ser75 in human Y79 retinoblastoma cells. J. Biochem.
126,957
-961.
Kleihues, P., and Ohgaki, H. (1999) Primary and secondary glioblastoma: From concept to clinical diagnosis. Neuro-Oncology [serial online], Doc. 98-18, January 19, 1999. URL neuro-oncology.mc.duke.edu. Neuro-Oncology 1,44 -51.[Abstract]
Kordek, R., Hironishi, M., Liberski, P.P., Yanagihara, R., and Gajdusek, D.C. (1996) Apoptosis in glial tumors as determined by in situ nonradioactive labeling of DNA breaks. Acta Neuropathol. 91,112 -116.[Medline]
Lazaro, J.B., Kitzmann, M., Poul, M.A., Vandromme, M., Lamb, N.J., and Fernandez, A. (1997) Cyclin dependent kinase 5, cdk5, is a positive regulator of myogenesis in mouse C2 cells. J. Cell Sci. 110,1251 -1260.[Abstract]
Lee, K.Y., and Johnston, R.N. (1997) Neurofilaments are part of the high molecular weight complex containing neuronal cdc2-like kinase (nclk). Brain Res. 773,197 -202.[CrossRef][ISI][Medline]
Lee, K.Y., Helbing, C.C., Choi, K.S., Johnston, R.N., and Wang,
J.H. (1997) Neuronal Cdc2-like kinase (Nclk) binds and
phosphorylates the retinoblastoma protein. J. Biol.
Chem. 272,5622
-5626.
Levee, M.G., Dabrowska, M.I., Lelli, J.L., Jr., and Hinshaw, D.B. (1996) Actin polymerization and depolymerization during apoptosis in HL-60 cells. Am. J. Physiol. 271,C1981 -C1992.
Lew, J., and Wang, J.H. (1995) Neuronal cdc2-like kinase. Trends Biochem. Sci. 20, 33-37.[CrossRef][ISI][Medline]
Lew, J., Beaudette, K., Litwin, C.M.E., and Wang, J.H.
(1992) Purification and characterization of a novel
proline-directed protein kinase from bovine brain. J. Biol.
Chem. 267,13383
-13390.
Lew, J., Huang, Q.Q., Qi, Z., Winkfein, R.J., Aebersold, R., Hunt, T., and Wang J. H. (1994) A brain-specific activator of cyclin-dependent kinase 5. Nature 371,423 -426.[CrossRef][Medline]
Lew, J., Qi, Z., Huang, Q.Q., Paudel, H., Matsuura, I., Matsushita, M., Zhu, X., and Wang J.H. (1995) Structure, function, and regulation of neuronal Cdc2-like protein kinase. Neurobiol. Aging 16,263 -268.[CrossRef][ISI][Medline]
Lopes, M.B., Frankfurter, A., Zientek, G.M., and Herman, M.M. (1992) The presence of neuron-associated microtubule proteins in the human U-251 MG cell line: A comparative neuroblot and immunohistochemical study. Mol. Chem. Neuropathol. 17,273 -287.[ISI][Medline]
Matsubara, M., Kusubata, M., Ishiguro, K., Uchida, T., Titani, K.,
and Taniguchi, H. (1996) Site-specific phosphorylation of
synapsin I by mitogen-activated protein kinase and Cdk5 and its effects on
physiological functions. J. Biol. Chem.
271,21108
-21113.
Meyerson, M., Enders, G.H., Wu, C.L., Su, L.K., Gorka, C., Nelson, C., Harlow, E., and Tsai L. (1992) A family of human cdc2-related protein kinases. EMBO J. 11,2909 -2917.[ISI][Medline]
Miyajima, M., Nornes, H.O., and Neuman, T. (1995) Cyclin E is expressed in neurons and forms complexes with cdk5. Neuroreport 6,1130 -1132.[ISI][Medline]
Nakamura, S., Kawamoto, Y., Nakano, S., Ikemoto, A., Akiguchi, I.,
and Kimura, J. (1997) Cyclin-dependent kinase 5 in Lewy body-like
inclusions in anterior horn cells of a patient with sporadic amyotrophic
lateral sclerosis. Neurology
48,267
-270.
Nakamura, S., Kawamoto, Y., Nakano, S., Akiguchi, I., and Kimura J. (1998) Cyclin-dependent kinase 5 and mitogen-activated protein kinase in glial cytoplasmic inclusions in multiple system atrophy. J. Neuropathol. Exp. Neurol. 57,690 -698.[ISI][Medline]
Nikolic, M., Dudek, H., Kwon, Y.T., Ramos, Y.F., and Tsai, L.H.
(1996) The cdk5/p35 kinase is essential for neurite outgrowth
during neuronal differentiation. Genes Dev.
10,816
-825.
Ohshima, T., Ward, J.M., Huh, C.G., Longenecker, G., Veeranna,
Pant, H.C., Brady, R.O., Martin, L.J., and Kulkarni, A.B. (1996)
Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal
corticogenesis, neuronal pathology and perinatal death. Proc. Natl.
Acad. Sci. U.S.A. 93,11173
-11178.
Paglini, G., Pigino, G., Kunda, P., Morfini, G., Maccioni, R.,
Quiroga, S., Ferreira, A., and Caceres, A. (1998) Evidence for
the participation of the neuron-specific CDK5 activator p35 during
laminin-enhanced axonal growth. J. Neurosci.
18,9858
-9869.
Patrick, G.N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P., and Tsai, L.-H. (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402,615 -622.[CrossRef][Medline]
Paudel, H.K., Lew, J., Ali, Z., and Wang, J.H. (1993)
Brain proline-directed protein kinase phosphorylates tau on sites that are
abnormally phosphorylated in tau associated with Alzheimer's paired helical
filaments. J. Biol. Chem.
268,23512
-23518.
Philpott, A., Porro, E.B., Kirschner, M.W., and Tsai, L.H.
(1997) The role of cyclin-dependent kinase 5 and a novel
regulatory subunit in regulating muscle differentiation and patterning.
Genes Dev. 11,1409
-1421.
Qi, Z., Huang, Q.Q., Lee, K.Y., Lew, J., and Wang J.H.
(1995) Reconstitution of neuronal Cdc2-like kinase from
bacteria-expressed Cdk5 and an active fragment of the brain-specific
activator: Kinase activation in the absence of Cdk5 phosphorylation.
J. Biol. Chem. 270,10847
-10854.
Shetty, K.T., Link, W.T., and Pant, H.C. (1993)
Cdc2-like kinase from rat spinal cord specifically phosphorylated KSPXK motifs
in neurofilament proteins: Isolation and characterization. Proc.
Natl. Acad. Sci. U.S.A. 90,6844
-6848.
Shetty, K.T., Kaech, S., Link, W.T., Jaffe, H., Flores, C.M., Wray, S., Pant, H.C., and Beushausen, S. (1995) Molecular characterization of a neuronal-specific protein that stimulates the activity of Cdk5. J. Neurochem. 64,1988 -1995.[ISI][Medline]
Shirvan, A., Ziv, I., Zilkha-Falb, R., Machlyn, T., Barzilai, A., and Melamed, E. (1998) Expression of cell cycle-related genes during neuronal apoptosis: Is there a distinct pattern? Neurochem. Res. 23,767 -777.[CrossRef][ISI][Medline]
Shuang, R., Zhang, L., Fletcher, A., Groblewski, G.E., Pevsner, J.,
and Stuenkel, E.L. (1998) Regulation of Munc-18/syntaxin 1A
interaction by cyclin-dependent kinase 5 in nerve endings. J. Biol.
Chem. 273,4957
-4966.
Songyang, Z., Lu, K.P., Kwon, Y.T., Tsai, L.H., Filhol, O., Cochet, C., Brickey, D.A., Soderling, T.R., Bartleson, C., Graves, D.J., DeMaggio, A.J., Hoekstra, M.F., Blenis, J., Hunter, T., and Cantley, L.C. (1996) A structural basis for substrate specificities of protein Ser/Thr kinases: Primary sequence preference of casein kinases I and II, NIMA, phosphorylase kinase, calmodulin-dependent kinase II, CDK5, and Erk1. Mol. Cell. Biol. 16,6486 -6493.[Abstract]
Stein, G.H. (1979) T98G: An anchorage-independent human tumor cell line that exhibits stationary phase G1 arrest in vitro. J. Cell. Physiol. 99,43 -54.[CrossRef][ISI][Medline]
Sun, D., Leung, C.L., and Liem, R.K.H. (1996)
Phosphorylation of the high molecular weight neurofilament protein (NF-H) by
Cdk5 and p35. J. Biol. Chem.
271,14245
-14251.
Tachibana, O., Lampe, J., Kleihues, P., and Ohgaki, H. (1996) Preferential expression of Fas/APO1 (CD95) and apoptotic cell death in perinecrotic cells of glioblastoma multiforme. Acta Neuropathol. 92,431 -434.[CrossRef][Medline]
Tang, D., and Wang, J.H. (1996) Cyclin-dependent kinase 5 (Cdk5) and neuron-specific Cdk5 activators. Prog. Cell Cycle Res. 2,205 -216.[Medline]
Tang, D., Yeung, J., Lee, K.Y., Matsushita, M., Matsui, H.,
Tomizawa, K., Hatase, O., and Wang, J.H. (1995) An isoform of the
neuronal cyclin-dependent kinase 5 (Cdk5) activator. J. Biol.
Chem. 270,26897
-26903.
Tang, D., Lee, K.Y., Qi, Z., Matsuura, I., and Wang, J.H. (1996) Neuronal Cdc2-like kinase: From cell cycle to neuronal function. Biochem. Cell Biol. 74,419 -429.[ISI][Medline]
Tang, D., Chun, A.C.S., Zhang, M., and Wang, J.H.
(1997) Cyclin-dependent kinase 5 (Cdk5) activation domain of
neuronal Cdk5 activator: Evidence of the existence of cyclin fold in neuronal
Cdk5a activator. J. Biol. Chem.
272,12318
-12327.
Tohyama, T., Lee, V.M.Y., and Trojanowski, J.Q. (1993) Co-expression of low molecular weight neurofilament protein and glial fibrillary acidic protein in established human glioma cell lines. Am. J. Pathol. 142,883 -892.[Abstract]
Tsai, L.H., Takahashi, T., Caviness, V.S., Jr., and Harlow, E. (1993) Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system. Development 119,1029 -1040.[Abstract]
Tsai, L.H., Delalle, I., Caviness, V.S., Jr., Chae, T., and Harlow, E. (1994) p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371,419 -423.[CrossRef][Medline]
Uchida, T., Ishiguro, K., Ohnuma, J., Takamatsu, M., Yonekura, S., and Imahori, K. (1994) Precursor of cdk5 activator, the 23 kDa subunit of tau protein kinase II: Its sequence and developmental change in brain. FEBS Lett. 355,35 -40.[CrossRef][ISI][Medline]
Van Engeland, M., Kuijpers, H.J.H., Ramaekers, F.C.S., Reutelingsperger, C.P.M., and Schutte, B. (1997) Plasma membrane alterations and cytoskeletal changes in apoptosis. Exp. Cell Res. 235,421 -430.[CrossRef][ISI][Medline]
Veeranna, Grant, P., and Pant, H.C. (1997) Expression of p67 (Munc-18), Cdk5, P-NFH and syntaxin during development of the rat cerebellum. Dev. Neurosci. 19,172 -183.[ISI][Medline]
Xiong, Y., Zhang, H., and Beach, D. (1992) D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell 71,505 -514.[CrossRef][ISI][Medline]
Yin, M.-B., Toth, K., Cao, S., Guo, B., Frank, C., Slocum, H.K., and Rustum, Y.M. (1999) Involvement of cyclin D1-cdk5 overexpression and MCM3 cleavage in bax-associated spontaneous apoptosis and differentiation in an A253 human head and neck carcinoma xenograft model. Int. J. Cancer 83,341 -348.[CrossRef][ISI][Medline]
Zhang, Q., Ahuja, H.S., Zakeri, Z.F., and Wolgemuth, D.J. (1997) Cyclin-dependent kinase 5 is associated with apoptotic cell death during development and tissue remodeling. Dev. Biol. 183,222 -233.[CrossRef][ISI][Medline]
This article has been cited by other articles:
|
|
 |
|
  R. Liu, B. Tian, M. Gearing, S. Hunter, K. Ye, and Z. Mao Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion PNAS, May 27, 2008; 105(21): 7570 - 7575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Sandal, C. Stapnes, H. Kleivdal, L. Hedin, and S. O. Doskeland A Novel, Extraneuronal Role for Cyclin-dependent Protein Kinase 5 (CDK5). MODULATION OF cAMP-INDUCED APOPTOSIS IN RAT LEUKEMIA CELLS J. Biol. Chem., May 31, 2002; 277(23): 20783 - 20793. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
