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1.  Fgfr4 is required for effective muscle regeneration in vivo: Delineation of a MyoD-Tead2-Fgfr4 transcriptional pathway 
The Journal of biological chemistry  2005;281(1):429-438.
Fgfr4 has been shown to be important for appropriate muscle development in chick limb buds, however, Fgfr4 null mice show no phenotype. Here, we show that staged induction of muscle regeneration in Fgfr4 null mice becomes highly abnormal at the time point when Fgfr4 is normally expressed. By 7 days of regeneration, differentiation of myotubes became poorly coordinated and delayed by both histology and embryonic myosin heavy chain staining. By 14 days, much of the muscle was replaced by fat and calcifications. To begin to dissect the molecular pathways involving Fgfr4, we queried the promoter sequences for transcriptional factor binding sites, and tested candidate regulators in a 27 time point regeneration series. The Fgfr4 promoter region contained a Tead protein binding site (M-CAT 5′-CATTCCT-3′), and Tead2 showed induction during regeneration commensurate with Fgfr4 regulation. Co-transfection of Tead2 and Fgfr4 promoter reporter constructs into C2C12 myotubes showed Tead2 to activate Fgfr4, and mutation of the M-CAT motif in the Fgfr4 promoter abolished these effects. Immunostaining for Tead2 showed timed expression in myotube nuclei consistent with the mRNA data. Query of the expression timing and genomic sequences of Tead2 suggested direct regulation by MyoD, and, consistent with this, MyoD directly bound to two strong E-boxes in the first intron of Tead2 by chromatin immunoprecipitation assay. Moreover, co-transfection of MyoD and Tead2 intron reporter constructs into 10T1/2 cells activated reporter activity in a dose dependent manner. This activation was greatly reduced when the two E-boxes were mutated. Our data suggest a novel MyoD-Tead2-Fgfr4 pathway important for effective muscle regeneration.
PMCID: PMC1892582  PMID: 16267055
Muscle regeneration; Tead; TEF; Fgfr; MyoD; Microarray
2.  Clinicopathological significance of FHIT protein expression in gastric adenocarcinoma patients 
AIM: To investigate the expression of fragile histidine triad (FHIT) protein, and the possible relationship between FHIT expression and clinicopathological indices in gastric carcinoma.
METHODS: FHIT protein expression was examined in 76 cases of gastric carcinoma, 58 cases of intraepithelial neoplasia, and 76 cases of corresponding normal mucosae by immunohistochemical method to analyze its relationship to histological grade, clinical stage, metastatic status and prognosis.
RESULTS: The FHIT protein expression was positive in 28/76 (36.8%) cases of adenocarcinoma tissue, 22/58 (37.9%) cases of adjacent dysplastic tissue and 76/76 (100%) cases of distal normal gastric mucosa. There was a significant difference in the expression of FHIT protein between cancer or adjacent intraepithelial neoplasia and normal gastric mucosa (P = 0.000). FHIT protein expression was found in 64.3% (18/28) of grades I and II cancers, and 20.8% (10/48) of grade III cancers (P = 0.000), in 56.3% (18/32) of stages I and II cancers and 22.7% (10/44) of stages III and IV cancers (P = 0.004), and in 63.6% (14/22) of cancers without metastasis but only 25.9% (14/54) of those with metastasis (P = 0.003). The significant difference in the expression of FHIT was found between histological grade, clinical stage and metastatic status of cancer. Follow-up data showed that there was a significant difference in median survival time between cancer patients with expression of FHIT (71 mo) and those without (33 mo, log rank = 20.78, P = 0.000).
CONCLUSION: FHIT protein is an important tumor suppressor protein. Loss of FHIT protein expression may be associated with carcinogenesis, invasion, metastasis and prognosis of gastric adenocarcinoma.
PMCID: PMC4481500  PMID: 16237777
Gastric cancer; Gene expression; FHIT; Prognosis

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