title: Cancer susceptibility polymorphism of p53 at codon 72 affects phosphorylation and degradation of p53 protein.
abstract: The common polymorphism of p53 at codon 72, either encoding proline or arginine, has drawn attention as a genetic factor associated with clinical outcome or cancer risk for the last 2 decades. We now show that these two polymorphic variants differ in protein structure, especially within the N-terminal region and, as a consequence, differ in post-translational modification at the N terminus. The arginine form (p53-72R) shows significantly enhanced phosphorylation at Ser-6 and Ser-20 compared with the proline form (p53-72P). We also show diminished Mdm2-mediated degradation of p53-72R compared with p53-72P, which is at least partly brought about by higher levels of phosphorylation at Ser-20 in p53-72R. Furthermore, enhanced p21 expression in p53-72R-expressing cells, which is dependent on phosphorylation at Ser-6, was demonstrated. Differential p21 expression between the variants was also observed upon activation of TGF-β signaling. Collectively, we demonstrate a novel molecular difference and simultaneously suggest a difference in the tumor-suppressing function of the variants.
authors: Radiobiology Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Tokyo 104-0045, Japan.
authors: Chikako
authors: C
authors: Ozeki
authors: Yuichiro
authors: Y
authors: Sawai
authors: Tatsuhiro
authors: T
authors: Shibata
authors: Takashi
authors: T
authors: Kohno
authors: Koji
authors: K
authors: Okamoto
authors: Jun
authors: J
authors: Yokota
authors: Fumio
authors: F
authors: Tashiro
authors: Sei-ichi
authors: S
authors: Tanuma
authors: Ryuichi
authors: R
authors: Sakai
authors: Tatsuya
authors: T
authors: Kawase
authors: Issay
authors: I
authors: Kitabayashi
authors: Yoichi
authors: Y
authors: Taya
authors: Rieko
authors: R
authors: Ohki
mesh_terms: D002460:Cell Line; D003062:Codon; D020022:Genetic Predisposition to Disease; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D011499:Protein Processing, Post-Translational; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D003062:Codon; C495901:TP53 protein, human; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2