Cdk5在电磁暴露致神经细胞损伤的作用初步探讨
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摘要
目的:随着科技的进步和发展,各类办公自动化设备、移动通讯设备、家用电器迅速进入我们的生活,在方便了生活的同时,也使我们更多地接触到电磁暴露。因此,电磁暴露的生物效应、效应机理及其防护正逐渐成为热点课题。我室以往的研究显示,电磁暴露作用的靶点包括神经系统、血液系统、生殖系统、免疫系统等,尤以电磁暴露对神经系统的影响最为显著,并且神经细胞损伤是电磁暴露致神经系统功能障碍的主要原因之一。细胞周期素依赖性蛋白激酶5(Cdk5)在神经系统表达最为丰富,其正常的活性是维系神经系统正常发育及功能所必须的。近年来有研究表明Cdk5及其活化亚基可能参与神经细胞的损伤。而在此前尚未有在电磁暴露致神经细胞损伤模型中关于Cdk5及其活化亚基的报道。本课题旨在对Cdk5及其活化亚基在电磁暴露致神经细胞损伤中的作用做初步探讨,从而为探索电磁暴露致神经细胞损伤的机制提供新的线索。
方法:①采用峰值功率密度为90 W/cm~2电磁暴露处理原代培养的大鼠皮层神经细胞10 min制作细胞致伤模型。②应用CCK-8试剂盒,分析电磁暴露后神经细胞细胞活性变化。③应用TUNEL试剂盒及Hoechst荧光染料双染,观察电磁暴露致神经细胞凋亡的作用。④应用RT-PCR及Western-blot技术,分析电磁暴露后不同时相点神经细胞Cdk5 mRNA及蛋白含量。⑤采用液闪法,检测电磁暴露后不同时相点神经细胞Cdk5的活性。⑥应用Western-blot技术,检测电磁暴露后不同时相点神经细胞Cdk5的活化亚基p35和p25蛋白含量。⑦用Cdk5抑制剂Roscovitine预处理后观察电磁暴露致神经细胞损伤情况的变化。
结果:①电磁暴露可导致神经细胞细胞活性在暴露后6h、12h和24h显著降低。②电磁暴露可导致神经细胞凋亡率升高,尤其以暴露后12、24h最为显著。以上两个结果提示电磁暴露对神经细胞有明显损伤效应,并呈时效特征。③电磁暴露后,神经细胞Cdk5 mRNA及蛋白含量在各个时相点与假暴露组相比均无显著性变化。④电磁暴露后,神经细胞Cdk5的活性在暴露后3h和6h明显升高。⑤电磁暴露后,神经细胞Cdk5活化亚基p25的蛋白含量在暴露后0h、3h和6h明显升高,而p35的蛋白含量无明显变化。结合Cdk5活性的变化趋势,提示电磁暴露可能是通过增加p25蛋白含量从而使Cdk5的活性升高。⑥给予Cdk5抑制剂Roscovitine预处理后,可部分拮抗电磁暴露引起的神经细胞细胞活性的下降,但不能显著减轻电磁暴露所引起的神经细胞凋亡率的增加。
结论:电磁暴露可以明显引起神经细胞的损伤及扰乱细胞周期素依赖性蛋白激酶5的活性及其活化亚基p25的蛋白含量,同时Cdk5抑制剂可以部分拮抗电磁暴露所致的神经细胞损伤效应。本研究提示电磁暴露可能通过影响p25/Cdk5的活性从而导致神经细胞的损伤,这些结果为研究电磁暴露致神经细胞损伤的机理以及防护措施提供了新的线索。
Objectives: With the development of science and technology, a lot of electrical appliances such as mobile phone, microwave oven, etc. step into our daily life rapidly, which lead more and more people exposing to electromagnetic radiation. The nervous syetem is one of the most sensitive targets of electromagnetic exposure. Electromagnetic exposure can cause learning and memory impairment which may result from neuron injury. Though the study on electromagnetic exposure bioeffect has been performed for many years, the bioeffects, pathological mechanisms of neuron injury induced by electromagnetic exposure is not well established yet. Cdk5 is most abundant in the nervous system and it appears to be indispensable for normal neural development and function. Present essentially in post-mitotic neurons, its normal activity is obligatory for neuronal migration and differentiation in developing brain. Studies showed that the deregulation of Cdk5 and its activators might be involved in the process of neuron injury (especially neuron apoptosis). Recently, there is not any study focus on the changes of Cdk5 and its activators p35 and p25 are involved in neuron injury induced by electromagnetic exposure.This study may provide new clues for studying the electromagnetic exposure bioeffect.
Methods: (1)The rat primary cortical neurons were cultured for 8 days and then were exposed to 90 W/cm~2 electromagnetic exposure for 10 min. (2) Effects of electromagnetic exposure on cellular viability of neurons were evaluated by CCK-8 Kit. (3) Effects of electromagnetic exposure on the rate of apoptosis of neurons were determined by TUNEL and Hoechst fluorescence staining. (4) Alterations of the mRNA level and the protein level of Cdk5 in neurons at different time points after electromagnetic exposure were studied by RT-PCR and Western-blot respectively. (5) Alterations of the activity of Cdk5 in neurons at different time points after electromagnetic exposure were studied by liquid scintillation counting. (6)Alterations of the protein levels of p35 and p25 in neurons at different time points after electromagnetic exposure were studied by Western-blot. (7) Neurons were pretreated with Cdk5 inhibitor Roscovitine, the cellular viability and the rate of apoptosis were observed after electromagnetic exposure.
Results: (1) The cellular viability of neurons significantly decreased at 6h, 12h and 24h after electromagnetic exposure. (2) Electromagnetic exposure led to increasing of the rate of apoptosis, which is the most marked at 12h and 24h after electromagnetic exposure. (3) Electromagnetic exposure did not induce significant change in neither the mRNA level nor the protein level of Cdk5. (4) At 3h and 6h after electromagnetic exposure, the activity of Cdk5 significantly increased by 97% and 51% respectively. (5) Electromagnetic exposure did not induce significant change in the protein level of p35, but the protein level of p25 significantly increased at 0h, 3h and 6h after electromagnetic exposure. (6) Cdk5 inhibitor Roscovitine pretreatment partly reversed the neuron injury induced by electromagnetic exposure.
Conclusions: Electromagnetic exposure can decrease the cellular viability and increase the rate of neuron apoptosis as well as disturb the activity of Cdk5 and the protein level of p25 in neurons,and Cdk5 inhibitor Roscovitine pretreatment partly reversed the neuron injury induced by electromagnetic exposure. The results suggest that electromagnetic exposure might lead to neuron injury through Cdk5 and p25 mediated signal pathway.These data provides some new clues to investigate the mechanisms of neuron injury induced by electromagnetic exposure and develop clinical approaches for treatments of neural injury induced by electromagnetic exposure.
方法:①采用峰值功率密度为90 W/cm~2电磁暴露处理原代培养的大鼠皮层神经细胞10 min制作细胞致伤模型。②应用CCK-8试剂盒,分析电磁暴露后神经细胞细胞活性变化。③应用TUNEL试剂盒及Hoechst荧光染料双染,观察电磁暴露致神经细胞凋亡的作用。④应用RT-PCR及Western-blot技术,分析电磁暴露后不同时相点神经细胞Cdk5 mRNA及蛋白含量。⑤采用液闪法,检测电磁暴露后不同时相点神经细胞Cdk5的活性。⑥应用Western-blot技术,检测电磁暴露后不同时相点神经细胞Cdk5的活化亚基p35和p25蛋白含量。⑦用Cdk5抑制剂Roscovitine预处理后观察电磁暴露致神经细胞损伤情况的变化。
结果:①电磁暴露可导致神经细胞细胞活性在暴露后6h、12h和24h显著降低。②电磁暴露可导致神经细胞凋亡率升高,尤其以暴露后12、24h最为显著。以上两个结果提示电磁暴露对神经细胞有明显损伤效应,并呈时效特征。③电磁暴露后,神经细胞Cdk5 mRNA及蛋白含量在各个时相点与假暴露组相比均无显著性变化。④电磁暴露后,神经细胞Cdk5的活性在暴露后3h和6h明显升高。⑤电磁暴露后,神经细胞Cdk5活化亚基p25的蛋白含量在暴露后0h、3h和6h明显升高,而p35的蛋白含量无明显变化。结合Cdk5活性的变化趋势,提示电磁暴露可能是通过增加p25蛋白含量从而使Cdk5的活性升高。⑥给予Cdk5抑制剂Roscovitine预处理后,可部分拮抗电磁暴露引起的神经细胞细胞活性的下降,但不能显著减轻电磁暴露所引起的神经细胞凋亡率的增加。
结论:电磁暴露可以明显引起神经细胞的损伤及扰乱细胞周期素依赖性蛋白激酶5的活性及其活化亚基p25的蛋白含量,同时Cdk5抑制剂可以部分拮抗电磁暴露所致的神经细胞损伤效应。本研究提示电磁暴露可能通过影响p25/Cdk5的活性从而导致神经细胞的损伤,这些结果为研究电磁暴露致神经细胞损伤的机理以及防护措施提供了新的线索。
Objectives: With the development of science and technology, a lot of electrical appliances such as mobile phone, microwave oven, etc. step into our daily life rapidly, which lead more and more people exposing to electromagnetic radiation. The nervous syetem is one of the most sensitive targets of electromagnetic exposure. Electromagnetic exposure can cause learning and memory impairment which may result from neuron injury. Though the study on electromagnetic exposure bioeffect has been performed for many years, the bioeffects, pathological mechanisms of neuron injury induced by electromagnetic exposure is not well established yet. Cdk5 is most abundant in the nervous system and it appears to be indispensable for normal neural development and function. Present essentially in post-mitotic neurons, its normal activity is obligatory for neuronal migration and differentiation in developing brain. Studies showed that the deregulation of Cdk5 and its activators might be involved in the process of neuron injury (especially neuron apoptosis). Recently, there is not any study focus on the changes of Cdk5 and its activators p35 and p25 are involved in neuron injury induced by electromagnetic exposure.This study may provide new clues for studying the electromagnetic exposure bioeffect.
Methods: (1)The rat primary cortical neurons were cultured for 8 days and then were exposed to 90 W/cm~2 electromagnetic exposure for 10 min. (2) Effects of electromagnetic exposure on cellular viability of neurons were evaluated by CCK-8 Kit. (3) Effects of electromagnetic exposure on the rate of apoptosis of neurons were determined by TUNEL and Hoechst fluorescence staining. (4) Alterations of the mRNA level and the protein level of Cdk5 in neurons at different time points after electromagnetic exposure were studied by RT-PCR and Western-blot respectively. (5) Alterations of the activity of Cdk5 in neurons at different time points after electromagnetic exposure were studied by liquid scintillation counting. (6)Alterations of the protein levels of p35 and p25 in neurons at different time points after electromagnetic exposure were studied by Western-blot. (7) Neurons were pretreated with Cdk5 inhibitor Roscovitine, the cellular viability and the rate of apoptosis were observed after electromagnetic exposure.
Results: (1) The cellular viability of neurons significantly decreased at 6h, 12h and 24h after electromagnetic exposure. (2) Electromagnetic exposure led to increasing of the rate of apoptosis, which is the most marked at 12h and 24h after electromagnetic exposure. (3) Electromagnetic exposure did not induce significant change in neither the mRNA level nor the protein level of Cdk5. (4) At 3h and 6h after electromagnetic exposure, the activity of Cdk5 significantly increased by 97% and 51% respectively. (5) Electromagnetic exposure did not induce significant change in the protein level of p35, but the protein level of p25 significantly increased at 0h, 3h and 6h after electromagnetic exposure. (6) Cdk5 inhibitor Roscovitine pretreatment partly reversed the neuron injury induced by electromagnetic exposure.
Conclusions: Electromagnetic exposure can decrease the cellular viability and increase the rate of neuron apoptosis as well as disturb the activity of Cdk5 and the protein level of p25 in neurons,and Cdk5 inhibitor Roscovitine pretreatment partly reversed the neuron injury induced by electromagnetic exposure. The results suggest that electromagnetic exposure might lead to neuron injury through Cdk5 and p25 mediated signal pathway.These data provides some new clues to investigate the mechanisms of neuron injury induced by electromagnetic exposure and develop clinical approaches for treatments of neural injury induced by electromagnetic exposure.
引文
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12. Shea TB, Yabe JT, Ortiz D, Pimenta A, Loomis P, Goldman RD, Amin N Pant HC (2003) Cdk5 regulates axonal transport and phosphorylation of neurofilaments in cultured neurons. J Cell Sci 117:933-941.
13. Cheng K, Ip NY (2003) Cdk5: a new player at synapses. Neurosignals 12:18-190.
14. Shelton SB, Johnson GVW (2004) Cyclin-dependent kinase-5 in neurodegeneration. J Neurochem 88(6):1313-1326.
15. Weishaupt JH, Neusch C, Ba¨hr M (2002) Cdk5 and neuronal cell death. Cell Tissue Res 312(1):1-8.
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25. Morgan D (1995) Principals of Cdk regulation. Nature 374:131-134.
26. Xinrong F, Yuk-Kwan C, Dianbo Q, Yan Y, Nam SC, Robert ZQ (2006) Identification of nuclear import mechanisms for the neuronal Cdk5 activator. J Biol Chem 281(851):39014-39021.
27. Patrick GN, Zukerberg L, Nikolic M, Suzanne de la M, Dikkes P, Tsai L-H (1999) Conversion of P35 to P25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615-622.
28. Lee M-S, Tsai L-H (2001) Cdk5 at the Junction. Nat Neurosci 4:340-342.
29. Patzke H, Maddineni U, Ayala R, Morabito M, Janet V, Dikkes P, Ahlijanian MK, Tsai L-H (2003) Partial rescue of the P35-/- brain phenotype by low expression of a neuronal-specific enolase P25 transgene. J Neurosci 23(7):2769.
30. Dhavan R, Tsai L-H (2001) Decade of Cdk5. Nat Rev Mol Cell Biol 2(10):749-759.
31. Zukerberg LR, Patrick GN, Nikolic M, Humbert S, Wu CL, Lanier LM, Gertler FB, Vidal M, Van Etten RA,Tsai LH (2000) Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron 26:633-646.
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34. Patrick GN, Zhou P, Kwon YT, Howley PM, Tsai L-H (1998) P35, the neuronal- specific activator of Cdk5 is degraded by the ubiquitin-proteasome pathway. J Biol Chem 273(37):24057-24064.
35. Kamei H, Saito T, Ozawa M, Fujita Y, Asada A, Bibb J, Saido TC, Sorimachi H, Hisanaga S-i (2007) Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation. J Biol Chem 282(3):1687-1694.
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44. Van den Haute C, Spittaels K, Van Dorpe J, Lasrado R, Vandezande K, Laenen I, Geerts H, Van Leuven F(2000) Coexpression of human Cdk5 and its activator P35 with human protein tau in neurons in brain of triple transgenic mice. Neurobiol Dis 8(1):32-44.
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7. Smith DS, Greer PL, Tsai L-H (2001) Cdk5 on the brain. Cell Growth Differ 12:277-283.
8. Hallows JL, Chen K, DePinho RA, Vincent I (2003) Decreased cyclin-dependent kinase 5 (Cdk5) activity is accompanied by redistribution of Cdk5 and cytoskeletal proteins and increased cytoskeletal protein phosphorylation in P35 null mice. J Neurosci 2 (33):10633-10644.
9. Smith Deanna (2003) Cdk5 in neuroskeletal dynamics. Neurosignals 12:239-251.
10. Nikolic M, Dudek H, Kwon YT, Ramos YFM, Tsai L-H (1996) The Cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation. Genes Dev 7:816-825.
11. Barclay JW, Aldea M, Craig TJ, Morgan A, Burgoyne RD (2004) Regulation of the fusion pore conductance during exocytosis by cyclin-dependent kinase 5. J Biol Chem 279(40):41495-41503.
12. Shea TB, Yabe JT, Ortiz D, Pimenta A, Loomis P, Goldman RD, Amin N Pant HC (2003) Cdk5 regulates axonal transport and phosphorylation of neurofilaments in cultured neurons. J Cell Sci 117:933-941.
13. Cheng K, Ip NY (2003) Cdk5: a new player at synapses. Neurosignals 12:18-190.
14. Shelton SB, Johnson GVW (2004) Cyclin-dependent kinase-5 in neurodegeneration. J Neurochem 88(6):1313-1326.
15. Weishaupt JH, Neusch C, Ba¨hr M (2002) Cdk5 and neuronal cell death. Cell Tissue Res 312(1):1-8.
16. Brown NR, Noble ME, Endicott JA, Johnson LN (1999) The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases. Nat Cell Biol 1:438.
17. Shetty KT, Link WT, Pant HC (1993) cdc2-like kinase from rat spinal cord specifically phosphorylates KSPXK motifs in neurofilament proteins: isolation characterization. Proc Natl Acad Sci USA 90:6844.
18. Buzko O, Shokat KM (2002) A kinase sequence database: sequence alignments and family assignment.Bioinformatics 18:1274; Nature 1995 374:131.
19. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912.
20. Mapelli M, Musacchio A (2003) The structural perspective on Cdk5. Neurosignals 12:164-172.
21. Uchida T, Ishiguro K, Ohnuma J, Takamatsu M, Yonekura S, 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.
22. Lew J, Huang QQ, Qi Z, Winkfein RJ, Aebersold R, Hunt T, Wang JH (1994) A brain-specific activator of cyclin-dependent kinase 5. Nature 371:423-426.
23. Tang D, Yeung J, Lee KY, Matsushita M, Matsui H, Tomizawa K, Hatase O, Wang JH (1995) An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator. J Biol Chem 270:26897-26903.
24. Damu T, Jeffery Y, Ki-Young L, Masayuki M, Hideki M, Kazuhito T, Osamu H, Jerry HW (1996) An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator. J Biol Chem 270(45):26897-26903.
25. Morgan D (1995) Principals of Cdk regulation. Nature 374:131-134.
26. Xinrong F, Yuk-Kwan C, Dianbo Q, Yan Y, Nam SC, Robert ZQ (2006) Identification of nuclear import mechanisms for the neuronal Cdk5 activator. J Biol Chem 281(851):39014-39021.
27. Patrick GN, Zukerberg L, Nikolic M, Suzanne de la M, Dikkes P, Tsai L-H (1999) Conversion of P35 to P25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615-622.
28. Lee M-S, Tsai L-H (2001) Cdk5 at the Junction. Nat Neurosci 4:340-342.
29. Patzke H, Maddineni U, Ayala R, Morabito M, Janet V, Dikkes P, Ahlijanian MK, Tsai L-H (2003) Partial rescue of the P35-/- brain phenotype by low expression of a neuronal-specific enolase P25 transgene. J Neurosci 23(7):2769.
30. Dhavan R, Tsai L-H (2001) Decade of Cdk5. Nat Rev Mol Cell Biol 2(10):749-759.
31. Zukerberg LR, Patrick GN, Nikolic M, Humbert S, Wu CL, Lanier LM, Gertler FB, Vidal M, Van Etten RA,Tsai LH (2000) Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron 26:633-646.
32. Sharma P, Sharma M, Amin ND, Albers WR, Pant HC (1999b) Regulation of cyclin- dependent kinase 5 catalytic activity by phosphorylation. Proc Natl Acad Sci 96(20):11156-11160.
33. Lee MS, Nikolic M, Baptista CA, Lai E, Tsai LH, Massague J (1996) The brain- specific activator p35 allows Cdk5 to escape inhibition by p27Kip1 in neurons. Proc Natl Acad Sci USA 93:3259.
34. Patrick GN, Zhou P, Kwon YT, Howley PM, Tsai L-H (1998) P35, the neuronal- specific activator of Cdk5 is degraded by the ubiquitin-proteasome pathway. J Biol Chem 273(37):24057-24064.
35. Kamei H, Saito T, Ozawa M, Fujita Y, Asada A, Bibb J, Saido TC, Sorimachi H, Hisanaga S-i (2007) Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation. J Biol Chem 282(3):1687-1694.
36. Chen YZ, Kelz MB. Steffen C, Ang ES, Zeng L, Nestler EJ (2000) Induction of cyclin-dependent kinase 5 in the hippocampus by chronic electroconvulsive seizures: role of dFosB. J Neurosci 20:8965-8971.
37. Tokouka H et al (2000) Brain-derived neurotrophic factorinduced phosphorylation of neurofilament-H subunit in primary cultures of embryo rat cortical neurons. J Cell Sci 113:1059-1068.
38. Smith DS, Greer PL, Tsai L-H (2001) Cdk5 on the brain. Cell Growth Differ 12:277-283.
39. Nguyen MD, Boudreau M, Kriz J, Couillard-Despres S, Kaplan DR, Julien JP (2003) Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1. J Neurosci 23:2131-2140.
40. Neystat M, Rzhetskaya M, Oo TF, Kholodilov N, Yarygina O, Wilson A, El-Khodor BF, Burke RE (2001) Expression of cyclin-dependent kinase 5 and its activator P35 in models of induced apoptotic death in neurons of the substantia nigra in vivo. J Neurochem 77(6):1611-1625.
41. Shouqing L, Coralie V, Janet ED, David CR (2005) Cdk5 phosphorylation of Huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity. JCB 169(4):647-656.
42. Paudel HK, Lew J, Ali Z, Wang JH (1993) Brain prolinedirected 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.
43. Kerokoski P, Suuronen T, Salminen A, Soininen H, Pirttila T (2001) The levels of Cdk5 and p35 proteins and tau phosphorylation are reduced during neuronal apoptosis. Biochem Biophys Res Commun 280:998-1002.
44. Van den Haute C, Spittaels K, Van Dorpe J, Lasrado R, Vandezande K, Laenen I, Geerts H, Van Leuven F(2000) Coexpression of human Cdk5 and its activator P35 with human protein tau in neurons in brain of triple transgenic mice. Neurobiol Dis 8(1):32-44.
45. Iijima K, Ando K, Takeda S, Satoh Y, Seki T, Itohara S, Greengard P, Kirino Y, Nairn AC, Suzuki T (2000) Neuron-specific phosphorylation of Alzheimer’s beta-amyloid precursor protein by cyclin-dependent kinase 5. J Neurochem 75:1085-1091.
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