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FBXW7 mutations typically found in human cancers are distinct from alleles and disrupt lung development.

Davis H, Lewis A, Spencer-Dene B, Tateossian H, Stamp G, Behrens A, Tomlinson I - J. Pathol. (2011)

Bottom Line: In most cases, these mutations do not inactivate the protein, but are mono-allelic missense changes at specific arginine resides involved in substrate binding.Fbxw7(-/-) animals died of vascular abnormalities at E10.5.Fbxw7(R482Q) alleles are not functionally equivalent to heterozygous or homozygous alleles, and we propose that they are selected in tumourigenesis because they cause a selective or partial loss of FBXW7 function.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.

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Phenotype of R482Q and Fbxw7+/− E18.5 lungs. (A) H&E staining on E18.5 lung samples. Left panel: wild-type; middle panel: R482Q; right panel: Fbxw7  heterozygotes (Fbxw7+/−). Scale bars are 150 µm. The R482Q lungs have thickened alveolar septa, whereas the wild-type and Fbxw7+/− have normal-thickness alveolar septa. The graph shows a summary of the septal thickness in wild-type and R482Q E18.5 lungs. (B) Ki67 immunohistochemistry staining of wild-type (left panel) and R482Q (middle panel) E18.5 lungs. Scale bars are 150 µm. There is an increase in the percentage of Ki67-positive proliferating cells in the R482Q sample shown in the graph in the right panel (p = 0.0275, t-test). Error bars represent the SEM
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fig03: Phenotype of R482Q and Fbxw7+/− E18.5 lungs. (A) H&E staining on E18.5 lung samples. Left panel: wild-type; middle panel: R482Q; right panel: Fbxw7 heterozygotes (Fbxw7+/−). Scale bars are 150 µm. The R482Q lungs have thickened alveolar septa, whereas the wild-type and Fbxw7+/− have normal-thickness alveolar septa. The graph shows a summary of the septal thickness in wild-type and R482Q E18.5 lungs. (B) Ki67 immunohistochemistry staining of wild-type (left panel) and R482Q (middle panel) E18.5 lungs. Scale bars are 150 µm. There is an increase in the percentage of Ki67-positive proliferating cells in the R482Q sample shown in the graph in the right panel (p = 0.0275, t-test). Error bars represent the SEM

Mentions: We analysed E18.5 R482Q embryos for physiological and histological abnormalities to explain the perinatal lethality and noted a striking difference in the histology of the embryonic lungs (Figure 3A). R482Q embryos had thickened alveolar septa in comparison to their wild-type littermates. Wild-type lung septa had a mean width of 16.5 µm (range 2.8–41.7 µm) compared with 32.5 µm (range 8.3–88.9 µm) in R482Q animals (N = 32, p = 1.05 × 10−11, t-test).


FBXW7 mutations typically found in human cancers are distinct from alleles and disrupt lung development.

Davis H, Lewis A, Spencer-Dene B, Tateossian H, Stamp G, Behrens A, Tomlinson I - J. Pathol. (2011)

Phenotype of R482Q and Fbxw7+/− E18.5 lungs. (A) H&E staining on E18.5 lung samples. Left panel: wild-type; middle panel: R482Q; right panel: Fbxw7  heterozygotes (Fbxw7+/−). Scale bars are 150 µm. The R482Q lungs have thickened alveolar septa, whereas the wild-type and Fbxw7+/− have normal-thickness alveolar septa. The graph shows a summary of the septal thickness in wild-type and R482Q E18.5 lungs. (B) Ki67 immunohistochemistry staining of wild-type (left panel) and R482Q (middle panel) E18.5 lungs. Scale bars are 150 µm. There is an increase in the percentage of Ki67-positive proliferating cells in the R482Q sample shown in the graph in the right panel (p = 0.0275, t-test). Error bars represent the SEM
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757315&req=5

fig03: Phenotype of R482Q and Fbxw7+/− E18.5 lungs. (A) H&E staining on E18.5 lung samples. Left panel: wild-type; middle panel: R482Q; right panel: Fbxw7 heterozygotes (Fbxw7+/−). Scale bars are 150 µm. The R482Q lungs have thickened alveolar septa, whereas the wild-type and Fbxw7+/− have normal-thickness alveolar septa. The graph shows a summary of the septal thickness in wild-type and R482Q E18.5 lungs. (B) Ki67 immunohistochemistry staining of wild-type (left panel) and R482Q (middle panel) E18.5 lungs. Scale bars are 150 µm. There is an increase in the percentage of Ki67-positive proliferating cells in the R482Q sample shown in the graph in the right panel (p = 0.0275, t-test). Error bars represent the SEM
Mentions: We analysed E18.5 R482Q embryos for physiological and histological abnormalities to explain the perinatal lethality and noted a striking difference in the histology of the embryonic lungs (Figure 3A). R482Q embryos had thickened alveolar septa in comparison to their wild-type littermates. Wild-type lung septa had a mean width of 16.5 µm (range 2.8–41.7 µm) compared with 32.5 µm (range 8.3–88.9 µm) in R482Q animals (N = 32, p = 1.05 × 10−11, t-test).

Bottom Line: In most cases, these mutations do not inactivate the protein, but are mono-allelic missense changes at specific arginine resides involved in substrate binding.Fbxw7(-/-) animals died of vascular abnormalities at E10.5.Fbxw7(R482Q) alleles are not functionally equivalent to heterozygous or homozygous alleles, and we propose that they are selected in tumourigenesis because they cause a selective or partial loss of FBXW7 function.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Oxford University, Roosevelt Drive, Oxford OX3 7BN, UK.

Show MeSH
Related in: MedlinePlus