Definition of the p53 functional domains necessary for inducing apoptosis

Jianhui Zhu, Shunzhen Zhang, Jieyuan Jiang, Xinbin Chen

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

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 (ΔAD1) 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-(ΔAD2), which lacks activation domain 2, is inert in inducing apoptosis. p53-(AD2-ΔBD), which is defective in activation domain 2 and lacks the C-terminal basic domain, p53-(ΔAD2ΔBD), which lacks both activation domain 2 and the C-terminal basic domain, and p53-(ΔPRDΔBD), 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-(ΔAD1ΔBD) 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 anti-apoptotic genes. The C-terminal basic domain is required for maintaining this activation domain competent for transactivation or transrepression.

Original languageEnglish (US)
Pages (from-to)39927-39934
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number51
DOIs
StatePublished - Dec 22 2000
Externally publishedYes

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Cell Cycle Checkpoints
Proline
Chemical activation
Apoptosis
Cells
Transcriptional Activation
Genes
Mutation
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Definition of the p53 functional domains necessary for inducing apoptosis. / Zhu, Jianhui; Zhang, Shunzhen; Jiang, Jieyuan; Chen, Xinbin.

In: Journal of Biological Chemistry, Vol. 275, No. 51, 22.12.2000, p. 39927-39934.

Research output: Contribution to journalArticle

Zhu, Jianhui ; Zhang, Shunzhen ; Jiang, Jieyuan ; Chen, Xinbin. / Definition of the p53 functional domains necessary for inducing apoptosis. In: Journal of Biological Chemistry. 2000 ; Vol. 275, No. 51. pp. 39927-39934.
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AB - 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 (ΔAD1) 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-(ΔAD2), which lacks activation domain 2, is inert in inducing apoptosis. p53-(AD2-ΔBD), which is defective in activation domain 2 and lacks the C-terminal basic domain, p53-(ΔAD2ΔBD), which lacks both activation domain 2 and the C-terminal basic domain, and p53-(ΔPRDΔBD), 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-(ΔAD1ΔBD) 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 anti-apoptotic genes. The C-terminal basic domain is required for maintaining this activation domain competent for transactivation or transrepression.

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