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A Second p53 Binding Site in the Central Domain of Mdm2 Is Essential for p53 Ubiquitination
Author(s) -
Ma Jianhong,
Martin John D.,
Zhang Hong,
Auger Kurt A.,
Ho Thau F.,
Kirkpatrick Robert B.,
Grooms Michael H.,
Johanson Kyung O.,
Tummino Peter J.,
Copeland Robert A.,
Lai Zhihong
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a273-b
Subject(s) - mdm2 , transactivation , ubiquitin ligase , ubiquitin , dna ligase , binding site , chemistry , microbiology and biotechnology , binding domain , biology , biochemistry , transcription factor , dna , gene
Mdm2 negatively regulates p53 by inhibiting its transcriptional activity and promoting its degradation by functioning as an E3 ubiquitin ligase. The primary p53 binding site on mdm2 is located in its N‐terminal domain. Through binding to p53 at its N‐terminal transactivation domain, mdm2 directly blocks the transcriptional activation function of p53. To understand how the binding interaction between mdm2 and p53 is related to the mdm2‐catalyzed p53 ubiquitination, we compared the ubiquitin ligase activity and binding interaction of full length mdm2 (mdm2‐FL) and various N‐terminally truncated mdm2 constructs toward p53. Our results indicate that the interaction between the N‐terminal domains of mdm2 and p53 is not required for the mdm2‐catalyzed p53 ubiquitination. Our results further indicate a second p53 binding site on mdm2 that is critical for its ubiquitin ligase activity toward p53; this site is located between amino acids 211 and 361, a region that includes the acidic domain and the zinc finger region. This second mdm2‐p53 interaction site represents an alternative target for small molecule modulators of the mdm2‐p53 pathway.