Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
Compound
Query: UMLS:C0004135 (
ATM
)
13,001
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
AIMP3
(previously known as p18) was shown to up-regulate p53 in response to DNA damage. Here, we show that
AIMP3
couples oncogenic stresses to p53 activation to prevent cell transformation. Growth factor- or Ras-dependent induction of p53 was blocked by single allelic loss of
AIMP3
as well as by suppression of
AIMP3
.
AIMP3
heterozygous cells became susceptible to cell transformation induced by oncogenes such as Ras or Myc alone. The transformed AIMP3+/- cells showed severe abnormality in cell division and chromosomal structure. Thus,
AIMP3
plays crucial roles in p53-mediated tumor-suppressive response against oncogenic stresses via differential activation of
ATM
and ATR, and in the maintenance of genomic stability.
...
PMID:AIMP3 haploinsufficiency disrupts oncogene-induced p53 activation and genomic stability. 1684 34
Although
AIMP3
/p18 is normally associated with the multi-tRNA synthetase complex via its specific interaction with methionyl-tRNA synthetase, it also works as a tumor suppressor by interacting with
ATM
, the upstream kinase of p53. To understand the molecular interactions of
AIMP3
and the mechanisms involved, we determined the crystal structure of
AIMP3
at 2.0-angstroms resolution and identified its potential sites of interaction with
ATM
.
AIMP3
contains two distinct domains linked by a 7-amino acid (Lys57-Ser63) peptide, which contains a 3(10) helix. The 56-amino acid N-terminal domain consists of two helices into which three antiparallel beta strands are inserted, and the 111-amino acid C-terminal domain contains a bundle of five helices (Thr64-Tyr152) followed by a coiled region (Pro153-Leu169). Structural analyses revealed homologous proteins such as yeast glutamyl-tRNA synthetase, Arc1p, EF1Bgamma, and glutathione S-transferase and suggested two potential molecular binding sites. Moreover, mutations at the C-terminal putative binding site abolished the interaction between
AIMP3
and
ATM
and the ability of
AIMP3
to activate p53. Thus, this work identified the two potential molecular interaction sites of
AIMP3
and determined the residues critical for its tumor-suppressive activity through the interaction with
ATM
.
...
PMID:Determination of three-dimensional structure and residues of the novel tumor suppressor AIMP3/p18 required for the interaction with ATM. 1834 21
