Changes in c-Jun but not Bcl-2 family proteins in p53-dependent apoptosis of mouse cerebellar granule neurons induced by DNA damaging agent bleomycin

被引:40
作者
Araki, T
Enokido, Y
Inamura, N
Aizawa, S
Reed, JC
Hatanaka, H
机构
[1] Osaka Univ, Inst Prot Res, Div Prot Biosynth, Suita, Osaka 565, Japan
[2] Kumamoto Univ, Sch Med, Inst Mol Embryol & Genet, Dept Morphogenesis, Kumamoto 860, Japan
[3] Burnham Inst, Apoptosis & Cell Death Res Program, La Jolla, CA 92037 USA
关键词
DNA repair; cell cycle; programmed cell death; neurotrophin; neuronal cell death;
D O I
10.1016/S0006-8993(98)00231-5
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Tumor suppressor gene p53 is a critical regulator of the cellular response to DNA damage. To examine the function of p53 in postmitotic CNS neurons, we cultured cerebellar granule cells from 15-day-old wild type and p53-deficient mice, and analyzed changes of protein expression in apoptosis elicited by DNA damage. When cerebellar granule cells from wild type mice were treated with bleomycin, a DNA strand-break inducing agent, neuronal death occurred. In contrast, cells from p53-deficient mice were resistant to bleomycin-induced neuronal death. Furthermore, cells from p53 heterozygous mice showed an intermediate resistance between wild type and p53-deficient mice. These results show that p53 is required for the bleomycin-induced cerebellar granule cell death. To examine which proteins are involved in this apoptosis, we examined changes in protein levels of the Bcl-2 family, including Bcl-2, Bcl-X and Bax. The relative amounts of these proteins did not change after bleomycin treatment, suggesting that the changes in the levels of these Bcl-2 family proteins are not necessary for apoptosis in this system. In contrast, the levels of c-Jun protein significantly increased 6 h after treatment with bleomycin in wild type but not in p53-deficient cerebellar granule cells. These results raise the possibility that c-Jun is required for p53-dependent neuronal apoptosis induced by bleomycin. (C) 1998 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:239 / 247
页数:9
相关论文
共 55 条
[1]   TROPHIC FACTORS AND NEURONAL SURVIVAL [J].
BARDE, YA .
NEURON, 1989, 2 (06) :1525-1534
[2]   HYDROGEN-PEROXIDE MEDIATES AMYLOID-BETA PROTEIN TOXICITY [J].
BEHL, C ;
DAVIS, JB ;
LESLEY, R ;
SCHUBERT, D .
CELL, 1994, 77 (06) :817-827
[3]   BCL-X, A BCL-2-RELATED GENE THAT FUNCTIONS AS A DOMINANT REGULATOR OF APOPTOTIC CELL-DEATH [J].
BOISE, LH ;
GONZALEZGARCIA, M ;
POSTEMA, CE ;
DING, LY ;
LINDSTEN, T ;
TURKA, LA ;
MAO, XH ;
NUNEZ, G ;
THOMPSON, CB .
CELL, 1993, 74 (04) :597-608
[4]   THYMOCYTE APOPTOSIS INDUCED BY P53-DEPENDENT AND INDEPENDENT PATHWAYS [J].
CLARKE, AR ;
PURDIE, CA ;
HARRISON, DJ ;
MORRIS, RG ;
BIRD, CC ;
HOOPER, ML ;
WYLLIE, AH .
NATURE, 1993, 362 (6423) :849-852
[5]   CLONING AND STRUCTURAL-ANALYSIS OF CDNAS FOR BCL-2 AND A HYBRID BCL-2/IMMUNOGLOBULIN TRANSCRIPT RESULTING FROM THE T(14-18) TRANSLOCATION [J].
CLEARY, ML ;
SMITH, SD ;
SKLAR, J .
CELL, 1986, 47 (01) :19-28
[6]   INDUCTION OF APOPTOSIS IN CEREBELLAR GRANULE NEURONS BY LOW POTASSIUM - INHIBITION OF DEATH BY INSULIN-LIKE GROWTH FACTOR-I AND CAMP [J].
D'MELLO, SR ;
GALLI, C ;
CIOTTI, T ;
CALISSANO, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (23) :10989-10993
[7]  
Didier M, 1996, J NEUROSCI, V16, P2238
[8]   WAF1, A POTENTIAL MEDIATOR OF P53 TUMOR SUPPRESSION [J].
ELDEIRY, WS ;
TOKINO, T ;
VELCULESCU, VE ;
LEVY, DB ;
PARSONS, R ;
TRENT, JM ;
LIN, D ;
MERCER, WE ;
KINZLER, KW ;
VOGELSTEIN, B .
CELL, 1993, 75 (04) :817-825
[9]  
Enokido Y, 1997, J NEUROCHEM, V69, P246
[10]   APOPTOTIC CELL-DEATH OCCURS IN HIPPOCAMPAL-NEURONS CULTURED IN A HIGH OXYGEN ATMOSPHERE [J].
ENOKIDO, Y ;
HATANAKA, H .
NEUROSCIENCE, 1993, 57 (04) :965-972