Definition of the p53 functional domains necessary for inducing apoptosis

被引:98
作者
Zhu, JH [1 ]
Zhang, SZ [1 ]
Jiang, JY [1 ]
Chen, XB [1 ]
机构
[1] Med Coll Georgia, Inst Mol Biol & Genet, Augusta, GA 30912 USA
关键词
D O I
10.1074/jbc.M005676200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The p53 protein contains several functional domains necessary for inducing cell cycle arrest and apoptosis. The C-terminal basic domain within residues 364-393 and the proline-rich domain within residues 64-91 are required for apoptotic activity. In addition, activation domain 2 within residues 43-63 is necessary for apoptotic activity when the N-terminal activation domain 1 within residues 1-42 is deleted (Delta AD1) or mutated (AD1(-)). Here we have discovered that an activation domain 2 mutation at residues 53-54 (AD2(-)) abrogates the apoptotic activity but has no significant effect on cell cycle arrest. We have also found that p53-(Delta AD2), which lacks activation domain 2, is inert in inducing apoptosis. p53-(AD2(-)Delta BD), which is defective in activation domain 2 and lacks the C-terminal basic domain, p53-(Delta AD2 Delta BD), which lacks both activation domain 2 and the C-terminal basic domain, and p53-(Delta PRD Delta BD), which lacks both the proline-rich domain and the C-terminal basic domain, are also inert in inducing apoptosis. All four mutants are still capable of inducing cell cycle arrest, albeit to a lesser extent than wild-type p53. Interestingly, we have found that deletion of the N-terminal activation domain 1 alleviates the requirement of the C-terminal basic domain for apoptotic activity. Thus, we have generated a small but potent p53-(Delta AD1 Delta BD) molecule. Furthermore, we have determined that at least two of the three domains (activation domain 1, activation domain 2, and the proline-rich domain), are required for inducing cell cycle arrest. Taken together, our results suggest that activation domain 2 and the proline-rich domain form an activation domain for inducing pro-apoptotic genes or inhibiting antiapoptotic genes. The C-terminal basic domain is required for maintaining this activation domain competent for transactivation or transrepression.
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收藏
页码:39927 / 39934
页数:8
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