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: UNIPROT:P43146 (
tumour suppressor
)
5,935
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Aberrant splicing is frequently found in cancer, yet the biological consequences of such alterations are mostly undefined. Here we report that the Hippo-YAP signalling, a key pathway that regulates cell proliferation and organ size, is under control of a splicing switch. We show that
TEAD4
, the transcription factor that mediates Hippo-YAP signalling, undergoes alternative splicing facilitated by the
tumour suppressor
RBM4, producing a truncated isoform,
TEAD4
-S, which lacks an N-terminal DNA-binding domain, but maintains YAP interaction domain.
TEAD4
-S is located in both the nucleus and cytoplasm, acting as a dominant negative isoform to YAP activity. Consistently,
TEAD4
-S is reduced in cancer cells, and its re-expression suppresses cancer cell proliferation and migration, inhibiting tumour growth in xenograft mouse models. Furthermore,
TEAD4
-S is reduced in human cancers, and patients with elevated
TEAD4
-S levels have improved survival. Altogether, these data reveal a splicing switch that serves to fine tune the Hippo-YAP pathway.
...
PMID:A splicing isoform of TEAD4 attenuates the Hippo-YAP signalling to inhibit tumour proliferation. 2729 20
The Hippo pathway is a tumour-suppressive pathway and its inactivation is known to be associated with progression and metastasis of various cancers. LATS1/2 (large
tumour suppressor
homolog 1 and 2), YAP1 (Yes-associated protein 1), and
TEAD4
(TEA domain-containing sequence-specific transcription factors 4) are core components of the Hippo pathway, and their prognostic roles have not yet been studied in advanced gastric cancers (AGCs). A total of 318 surgically resected AGCs were retrieved. Immunolabelling for LATS1/2, YAP1 and
TEAD4
was compared with clinicopathological factors including patients' survival. High expression of YAP1 and
TEAD4
was identified in 108 (34.0%) and 131 (41.2%) cases, respectively, and 223 (70.1%) cases were negative for LATS1/2 expression. High YAP1 expression was significantly correlated with the presence of perineural invasion (p=0.032). High YAP1 and high
TEAD4
expressions were significantly associated with poor overall survival (p<0.001 and p=0.003, respectively), and negative LATS1/2 expression was also associated with poor overall survival (p=0.002). Combined expression of YAP1
high
LATS1/2
neg
showed the worst overall survival (p<0.001). Expression of YAP1
high
(HR=2.938; 95% CI 1.726-4.998; p<0.001), LATS1/2
neg
(HR=0.371; 95% CI 0.181-0.758; p=0.007), and combined YAP1
high
LATS1/2
neg
(HR=13.785; 95% CI 3.245-58.554; p<0.001) were independent poor prognostic factors of AGC patients. Combined or individual expression of YAP1, LATS1/2, and
TEAD4
can be used as prognostic markers of AGC patients.
...
PMID:High Yes-associated protein 1 with concomitant negative LATS1/2 expression is associated with poor prognosis of advanced gastric cancer. 3081 40
