The haploinsufficient tumor suppressor p18 upregulates p53 via interactions with ATM/ATR.
p18 was first identified as a factor associated with a macromolecular tRNA synthetase complex. Here we describe the mouse p18 loss-of-function phenotype and a role for p18 in the DNA damage response. Inactivation of both p18 alleles caused embryonic lethality, while heterozygous mice showed high susceptibility to spontaneous tumors. p18 ... was induced and translocated to the nucleus in response to DNA damage. Expression of p18 resulted in elevated p53 levels, while p18 depletion blocked p53 induction. p18 directly interacted with ATM/ATR in response to DNA damage. The activity of ATM was dependent on the level of p18, suggesting the requirement of p18 for the activation of ATM. Low p18 expression was frequently observed in different human cancer cell lines and tissues. These results suggest that p18 is a haploinsufficient tumor suppressor and a key factor for ATM/ATR-mediated p53 activation.
Mesh Terms:
Alleles, Amino Acyl-tRNA Synthetases, Animals, Apoptosis, Base Sequence, Cell Cycle, Cell Cycle Proteins, Cell Nucleus, Cell Proliferation, DNA Damage, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Knockout, Molecular Sequence Data, Protein-Serine-Threonine Kinases, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
Alleles, Amino Acyl-tRNA Synthetases, Animals, Apoptosis, Base Sequence, Cell Cycle, Cell Cycle Proteins, Cell Nucleus, Cell Proliferation, DNA Damage, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Knockout, Molecular Sequence Data, Protein-Serine-Threonine Kinases, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
Cell
Date: Jan. 28, 2005
PubMed ID: 15680327
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