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:C0677930 (
primary tumor
)
20,210
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Colorectal cancer (CRC) is one of the most common cancers that is characterized by a high mortality due to the strong metastatic potential of the
primary tumor
and the high rate of therapy resistance. Hereby, evasion of apoptosis is the primary underlying cause of reduced sensitivity of tumor cells to chemo- and radiotherapy. Using RNA affinity chromatography, we identified the tripartite motif-containing protein 25 (TRIM25) as a bona fide
caspase-2
mRNA-binding protein in colon carcinoma cells. Loss-of-function and gain-of-function approaches revealed that TRIM25 attenuates the protein levels of
caspase-2
without significantly affecting
caspase-2
mRNA levels. In addition, experiments with cycloheximide revealed that TRIM25 does not affect the protein stability of
caspase-2
. Furthermore, silencing of TRIM25 induced a significant redistribution of
caspase-2
transcripts from RNP particles to translational active polysomes, indicating that TRIM25 negatively interferes with
caspase-2
translation. Functionally, the elevation in
caspase-2
upon TRIM25 depletion significantly increased the sensitivity of colorectal cells to drug-induced intrinsic apoptosis as implicated by increased caspase-3 cleavage and cytochrome c release. Importantly, the apoptosis-sensitizing effects by transient TRIM25 knockdown were rescued by concomitant silencing of
caspase-2
, demonstrating a critical role of
caspase-2
. Inhibition of
caspase-2
by TRIM25 implies a survival mechanism that critically contributes to chemotherapeutic drug resistance in CRC.
...
PMID:Identification of TRIM25 as a Negative Regulator of Caspase-2 Expression Reveals a Novel Target for Sensitizing Colon Carcinoma Cells to Intrinsic Apoptosis. 3184 82
