The Haploinsufficient Tumor Suppressor p18 Upregulates p53 via Interactions with ATM/ATR

Abstract

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.

Determination of Three-dimensional Structure and Residues of the Novel Tumor Suppressor AIMP3/p18 Required for the Interaction with ATM

“…5, A and B). Although AIMP3 is necessary for the stability of MRS, it also functions as a positive regulator of the kinase activity of ATM (8). In addition, AIMP3 could target itself to form a homodimer, as implied by crystal packing shown in the present study and by previous yeast two-hybrid analyses (38).…”

“…It has been reported that AIMP3-heterozygous mice develop various cancers including lymphoma at high frequency and, furthermore, that the allelic deletion of AIMP3 is often observed in cancer patients including leukemia patients (8). To identify mutations affecting the interaction of AIMP3 with ATM, we isolated the gene encoding AIMP3 from 20 different chronic myeloid leukemia (CML) patients.…”

“…AIMP2/p38 has been shown to mediate transforming growth factor-␤ signaling for c-Myc down-regulation (7). AIMP3/p18 binds to the multi-ARS complex by specifically interacting with methionyltRNA synthetase (MRS) and is translocated to the nucleus to activate p53 through the interaction with kinases such as ATM (ataxia telangiectasia mutated) and ATR (ATM-and Rad3-related) in response to DNA damage (8) or oncogenic stress (9). To understand the multifunctionality and regulation of the components of the multi-ARS complex, it is important to determine the three-dimensional structures of the components as well as the whole complex.…”

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

“…Park et al (2005) showed that p18 regulates ATM-dependent p53 induction after DNA damage, and that ATM and ATR directly interact with p18 after UV and/or adriamycin treatment. ATM autophosphorylation was increased by the overexpression of p18, and disruption of p18 using antisense RNA caused a reduction in p53 phosphorylation after adriamycin treatment.…”

Antitumor effect of novel small chemical inhibitors of Snail-p53 binding in K-Ras-mutated cancer cells

“…Animal experiment was performed after obtaining approval from and following guidelines of the institute of animal care committee of Pusan National University. Histological tissue analysis was performed through basic procedure (Park et al, 2005).…”