The codon 47 polymorphism in p53 is functionally significant.
In addition to a common polymorphism at codon 72, the p53 tumor suppressor gene also contains a rare single nucleotide polymorphism at amino acid 47. Wild type p53 encodes proline at this residue, but in <5% of African Americans, this amino acid is serine. Notably, phosphorylation of the adjacent serine 46 by the proline-directed kinase p38 MAPK is known to greatly enhance the ability of p53 to induce apoptosis. Here we showed that the serine 47 polymorphic variant, which replaces the proline residue necessary for recognition by proline-directed kinases, is a markedly poorer substrate for phosphorylation on serine 46 by p38 MAPK. Consistent with this finding, we showed that the serine 47 variant has up to 5-fold decreased ability to induce apoptosis compared with wild type p53. Mechanistically, we found that this variant has decreased ability to transactivate two p53 target genes, p53AIP1 and PUMA, but not other p53 response genes; this is the first time that phosphorylation of serine 46 has been implicated in transactivation of PUMA by p53. Down-regulation of PUMA in cells with wild type p53 using short interfering RNAs reduced apoptosis in these cells to a level comparable to that in cells containing the serine 47 variant. The combined data indicated that, like the codon 72 polymorphism, the codon 47 polymorphism of p53 is functionally significant and may play a role in cancer risk, progression, and the efficacy of therapy.
Li
Xiaoxian
X
Cell and Developmental Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Dumont
Patrick
P
Della Pietra
Anthony
A
Shetler
Cory
C
Murphy
Maureen E
ME
D000595:Amino Acid Sequence; D001483:Base Sequence; D044383:Black People; D003062:Codon; D017931:DNA Primers; D006801:Humans; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D001741:Black or African American
D003062:Codon; D017931:DNA Primers; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases