C-terminus of p53 is required for G(2) arrest.
Mutation of four lysine residues in the p53 C-terminal domain inhibits MDM2-dependent ubiquitination of p53 and alters its subcellular distribution. This implies that modification (such as acetylation and phosphorylation) of amino acid residues in p53 C-terminal domain, regulate the biological functions of p53. In this study, we demonstrated that p53 with lysine residues 372, 373, 381, and 382 mutated to alanine (the A4 mutant) retained the transactivation activity of wild-type p53, although the transactivation activity of p21 promoter by the A4 mutant was slightly reduced. The inducible expression of wild-type p53 and the A4 mutant in H1299 cells caused growth inhibition due to cell-cycle arrest. Consistent with previous studies, the expression of wild-type p53 elicited G(1) and G(2) arrests. However, the cells expressing the A4 mutant underwent G(1) arrest but not G(2) arrest. Cyclin B1-associated kinase activity was reduced in cells expressing wild-type p53 but not A4, when the cells underwent G(2) arrest. This suggests that modification of the p53 C-terminal domain might inhibit p53-mediated G(2) arrest. In other words, p53 requires an intact C-terminus to induce G(2) arrest.
Nakamura
Seiichi
S
Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, Box 109, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas, TX 77030, USA.
Gomyo
Yoshihito
Y
Roth
Jack A
JA
Mukhopadhyay
Tapas
T
D000595:Amino Acid Sequence; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D004247:DNA / Q000032:analysis; D005434:Flow Cytometry; D016195:G2 Phase; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
C534699:CCNB1 protein, human; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D016159:Tumor Suppressor Protein p53; D004247:DNA; D001120:Arginine; D016203:CDC2 Protein Kinase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D008239:Lysine