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: EC:6.5.1.2 (
DNA ligase
)
2,749
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Glioblastoma Multiforme (GBM), the most common and lethal primary human brain tumor, exhibits multiple molecular aberrations. We report that loss of the transcription factor
GATA4
, a negative regulator of normal astrocyte proliferation, is a driver in glioma formation and fulfills the hallmarks of a tumor suppressor gene (TSG). Although
GATA4
was expressed in normal brain, loss of
GATA4
was observed in 94/163 GBM operative samples and was a negative survival prognostic marker.
GATA4
loss occurred through promoter hypermethylation or novel somatic mutations. Loss of
GATA4
in normal human astrocytes promoted high-grade astrocytoma formation, in cooperation with other relevant genetic alterations such as activated Ras or loss of TP53. Loss of
GATA4
with activated Ras in normal astrocytes promoted a progenitor-like phenotype, formation of neurospheres, and the ability to differentiate into astrocytes, neurons, and oligodendrocytes. Re-expression of
GATA4
in human GBM cell lines, primary cultures, and brain tumor-initiating cells suppressed tumor growth in vitro and in vivo through direct activation of the cell cycle inhibitor P21(CIP1), independent of TP53. Re-expression of
GATA4
also conferred sensitivity of GBM cells to temozolomide, a DNA alkylating agent currently used in GBM therapy. This sensitivity was independent of MGMT (O-6-methylguanine-DNA-methyltransferase), the
DNA repair enzyme
which is often implicated in temozolomide resistance. Instead,
GATA4
reduced expression of APNG (alkylpurine-DNA-N-glycosylase), a
DNA repair enzyme
which is poorly characterized in GBM-mediated temozolomide resistance. Identification and validation of
GATA4
as a TSG and its downstream targets in GBM may yield promising novel therapeutic strategies.
...
PMID:A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas. 2146 20
