A p53 Amino-Terminal Nuclear Export Signal Inhibited by DNA Damage-Induced Phosphorylation

The p53 protein is present in low amounts in normally growing cells and is activated in response to physiological insults. MDM2 regulates p53 either through inhibiting p53's transactivating function in the nucleus or by targeting p53 degradation in the cytoplasm. We identified a previously unknown nuclear export signal (NES) in the amino terminus of p53, spanning residues 11 to 27 and containing two serine residues phosphorylated after DNA damage, which was required for p53 nuclear export in colloboration with the carboxyl-terminal NES. Serine-15–phosphorylated p53 induced by ultraviolet irradiation was not exported. Thus, DNA damage–induced phosphorylation may achieve optimal p53 activation by inhibiting both MDM2 binding to, and the nuclear export of, p53.

[1]  Yoichi Taya,et al.  DNA Damage-Induced Phosphorylation of p53 Alleviates Inhibition by MDM2 , 1997, Cell.

[2]  M. Oren.  Regulation of the p53 Tumor Suppressor Protein* , 1999, The Journal of Biological Chemistry.

[3]  A. Levine,et al.  Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[4]  C. Sherr,et al.  Tumor surveillance via the ARF-p53 pathway. , 1998, Genes & development.

[5]  Stephen N. Jones,et al.  Regulation of p53 stability by Mdm2 , 1997, Nature.

[6]  Y. Xiong,et al.  Control of p53 ubiquitination and nuclear export by MDM2 and ARF. , 2001, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[7]  C. Prives.  Signaling to p53 Breaking the MDM2–p53 Circuit , 1998, Cell.

[8]  A. Levine,et al.  P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[9]  A. Levine.  p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[10]  A. Levine,et al.  Nuclear Export Is Required for Degradation of Endogenous p53 by MDM2 and Human Papillomavirus E6 , 1998, Molecular and Cellular Biology.

[11]  Roger Y Tsien,et al.  Identification of a signal for rapid export of proteins from the nucleus , 1995, Cell.

[12]  E. Appella,et al.  p53 transcriptional activity is essential for p53‐dependent apoptosis following DNA damage , 2000, The EMBO journal.

[13]  A. Levine,et al.  Nucleo‐cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein , 1998, The EMBO journal.

[14]  C. Maki,et al.  The MDM2 RING-finger domain is required to promote p53 nuclear export , 2000, Nature Cell Biology.

[15]  Hirofumi Tanaka,et al.  Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53 , 1997, FEBS letters.

[16]  A. Giaccia,et al.  The complexity of p53 modulation: emerging patterns from divergent signals. , 1998, Genes & development.

[17]  A. Levine,et al.  The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation , 1992, Cell.

[18]  Y. Xiong,et al.  Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53. , 1999, Molecular cell.

[19]  A. Levine,et al.  Several hydrophobic amino acids in the p53 amino-terminal domain are required for transcriptional activation, binding to mdm-2 and the adenovirus 5 E1B 55-kD protein. , 1994, Genes & development.

[20]  E. Appella,et al.  Phosphorylation of murine p53 at ser-18 regulates the p53 responses to DNA damage. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[21]  G. Wahl,et al.  A transactivation-deficient mouse model provides insights into Trp53 regulation and function , 2000, Nature Genetics.

[22]  K. Tsai,et al.  An intact HDM2 RING-finger domain is required for nuclear exclusion of p53 , 2000, Nature Cell Biology.

[23]  Yue Xiong,et al.  ARF Promotes MDM2 Degradation and Stabilizes p53: ARF-INK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways , 1998, Cell.

[24]  G. Wahl,et al.  A leucine‐rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking , 1999, The EMBO journal.

[25]  M. Oren,et al.  Mdm2 promotes the rapid degradation of p53 , 1997, Nature.

[26]  T. Halazonetis,et al.  Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. , 2000, Genes & development.

[27]  C. Prives,et al.  p53: puzzle and paradigm. , 1996, Genes & development.

[28]  R. Tjian,et al.  Repression of p53-mediated transcription by MDM2: a dual mechanism. , 1997, Genes & development.