Modification of serine 392 is a critical event in the regulation of p53 nuclear export and stability.
Although it has been shown that phosphorylations of p53 serine its residues are critical events for the regulation of their function, the specific biological effects of each of these phosphorylations, especially at serine 392, remain to be elucidated. Serine 392 has been proposed to play a role in the tetramerization of p53 and in the enhancement of its DNA-binding affinity. However, this is not consistent with other reports showing that substitution of serine 392 does not disrupt p53 function. These discrepancies suggest that modification of serine 392 may contribute to p53 activity through other transactivating pathways. In this study, we demonstrate that this C-terminal serine residue (p53-392S) in fact plays a critical role in the regulation of p53 stability such that substitution with alanine (p53-392A) strongly enhances p53 stability without disrupting mouse double minute 2 binding. Additionally, the p53-392A mutant is localized mainly in the nucleus, whereas both wild-type p53 and a glutamic acid mutant, p53-392E, are evenly distributed throughout the cytoplasm and nucleus. However, each of these p53 species had similar effects on both cell cycle inhibition and apoptosis, in response to either UV or adriamycin treatment. Moreover, p53-392A protein was resistant to E6-mediated degradation. Our results suggest that although serine 392 is not essential for the transactivation and nuclear import of p53, it exerts important effects upon p53 stability via the inhibition of its nuclear export mechanism.
National Genome Research Institute, National Institute of Health in Korea, Seoul, Republic of Korea.
Young-Youl
YY
Kim
Bum-Joon
BJ
Park
Dong-Joon
DJ
Kim
Woo-Hyang
WH
Kim
Soonhag
S
Kim
Kyung-Soo
KS
Oh
Joong-Yeon
JY
Lim
Joon
J
Kim
Chan
C
Park
Sang-Ick
SI
Park
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D017931:DNA Primers; D004355:Drug Stability; D005822:Genetic Vectors; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D016133:Polymerase Chain Reaction / Q000379:methods; D011471:Prostatic Neoplasms; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012694:Serine; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism*
D017931:DNA Primers; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D012694:Serine