Am J Cancer Res 2013;3(5):490-499
Original Article
Manic fringe inhibits tumor growth by suppressing Notch3 degradation in lung
cancer
Fuming Yi, Baru Amarasinghe, Thao P Dang
Division of Hematology and Medical Oncology, University of Virginia, Charlottesville, VA, USA
Received July 25, 2013; Accepted September 12, 2013; Epub November 1, 2013; Published November 15, 2013
Abstract: Notch signaling plays an essential role in development as well as cancer. We have previously shown that Notch3 is
important for lung cancer growth and survival. Notch receptors are activated through the interaction with their ligands, resulting in
proteolytic cleavage of the receptors. This interaction is modulated by Fringe, a family of fucose-specific β1,3 N-
acetylglucosaminyltransferases that modify the extracellular subunit of Notch receptors. Studies in developmental models
showed that Fringe enhances Notch’s response to Delta ligands at the expense of Jagged ligands. We observed that Manic
Fringe expression is down-regulated in lung cancer. Since Jagged1, a known ligand for Notch3, is often over-expressed in lung
cancer, we hypothesized that Fringe negatively regulates Notch3 activation. In this study, we show that re-expression of Manic
Fringe down-regulates Notch3 target genes HES1 and HeyL and reduces tumor phenotype in vitro and in vivo. The mechanism
for this phenomenon appears to be related to modulation of Notch3 protein stability. Proteasome inhibition reverses Manic
Fringe-induced protein turnover. Taken together, our data provide the first evidence that Manic Fringe functions as a tumor
suppressor in the lung and that the mechanism of its anti-tumor activity is mediated by inhibition of Notch3 activation.
(ajcr0000219).
Keywords: Jagged1, manic fringe, Notch3, lung cancer
Address correspondence to: Thao P Dang or Fuming Yi, Division of Hematology and Medical Oncology, University of Virginia,
707B MR6, 345 Crispell Drive, Charlottesville, VA 22908, USA. E-mail: td9w@virginia.edu (TPD); fy3d@virginia.edu (FY)
Original Article
Manic fringe inhibits tumor growth by suppressing Notch3 degradation in lung
cancer
Fuming Yi, Baru Amarasinghe, Thao P Dang
Division of Hematology and Medical Oncology, University of Virginia, Charlottesville, VA, USA
Received July 25, 2013; Accepted September 12, 2013; Epub November 1, 2013; Published November 15, 2013
Abstract: Notch signaling plays an essential role in development as well as cancer. We have previously shown that Notch3 is
important for lung cancer growth and survival. Notch receptors are activated through the interaction with their ligands, resulting in
proteolytic cleavage of the receptors. This interaction is modulated by Fringe, a family of fucose-specific β1,3 N-
acetylglucosaminyltransferases that modify the extracellular subunit of Notch receptors. Studies in developmental models
showed that Fringe enhances Notch’s response to Delta ligands at the expense of Jagged ligands. We observed that Manic
Fringe expression is down-regulated in lung cancer. Since Jagged1, a known ligand for Notch3, is often over-expressed in lung
cancer, we hypothesized that Fringe negatively regulates Notch3 activation. In this study, we show that re-expression of Manic
Fringe down-regulates Notch3 target genes HES1 and HeyL and reduces tumor phenotype in vitro and in vivo. The mechanism
for this phenomenon appears to be related to modulation of Notch3 protein stability. Proteasome inhibition reverses Manic
Fringe-induced protein turnover. Taken together, our data provide the first evidence that Manic Fringe functions as a tumor
suppressor in the lung and that the mechanism of its anti-tumor activity is mediated by inhibition of Notch3 activation.
(ajcr0000219).
Keywords: Jagged1, manic fringe, Notch3, lung cancer
Address correspondence to: Thao P Dang or Fuming Yi, Division of Hematology and Medical Oncology, University of Virginia,
707B MR6, 345 Crispell Drive, Charlottesville, VA 22908, USA. E-mail: td9w@virginia.edu (TPD); fy3d@virginia.edu (FY)
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American Journal of Cancer Research
| ISSN: 2156-6976 |