Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0004135 (
ATM
)
13,001
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Germline mutations in
ATM
(encoding the DNA-damage signaling kinase,
ataxia-telangiectasia
-mutated) increase Familial Pancreatic Cancer (FPC) susceptibility, and
ATM
somatic mutations have been identified in resected human pancreatic tumors. Here we investigated how Atm contributes to pancreatic cancer by deleting this gene in a murine model of the disease expressing oncogenic Kras (Kras
G12D
). We show that partial or total
ATM
deficiency cooperates with Kras
G12D
to promote highly metastatic pancreatic cancer. We also reveal that
ATM
is activated in pancreatic precancerous lesions in the context of DNA damage and cell proliferation, and demonstrate that
ATM
deficiency leads to persistent DNA damage in both precancerous lesions and primary tumors. Using low passage cultures from primary tumors and
liver metastases
we show that
ATM
loss accelerates Kras-induced carcinogenesis without conferring a specific phenotype to pancreatic tumors or changing the status of the tumor suppressors p53, p16
Ink4a
and p19
Arf
. However,
ATM
deficiency markedly increases the proportion of chromosomal alterations in pancreatic primary tumors and
liver metastases
. More importantly,
ATM
deficiency also renders murine pancreatic tumors highly sensitive to radiation. These and other findings in our study conclusively establish that
ATM
activity poses a major barrier to oncogenic transformation in the pancreas via maintaining genomic stability.
...
PMID:ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer. 2889 53
