Loss of PACS-2 delays regeneration in DSS-induced colitis but does not affect the ApcMin model of colorectal cancer

Sarah L. Dombernowsky; Jeanette Schwarz; Jacob Samsøe-Petersen; Reidar Albrechtsen; Kim B. Jensen; Gary Thomas; Marie Kveiborg

doi:10.18632/oncotarget.22661

Loss of PACS-2 delays regeneration in DSS-induced colitis but does not affect the Apc^Min model of colorectal cancer

Sarah L. Dombernowsky, Jeanette Schwarz, Jacob Samsøe-Petersen, Reidar Albrechtsen, Kim B. Jensen, Gary Thomas, Marie Kveiborg^*

^*Corresponding author for this work

4 Citations (Scopus)

173 Downloads (Pure)

Abstract

PACS-2 is a multifunctional sorting protein that mediates cell homeostasis. We recently identified PACS-2 in a functional genome-wide siRNA screen for novel regulators of the metalloproteinase ADAM17, the main sheddase for ligands of the ErbB receptor family. Of note, we showed that Pacs2^-/- mice have significantly reduced EGFR activity and proliferative index in the intestinal epithelium. As EGFR signaling is highly mitogenic for intestinal epithelial stem cells, and plays essential roles in intestinal epithelial regeneration and tumor development, we have now examined the role of PACS-2 in these processes. Specifically, we analyzed the role of Pacs2- deficiency in a DSS-induced colitis model as well as in the genetic Apc^Min colon cancer model. We now report that loss of PACS-2 delays tissue regeneration after colonic injury with little effect on key inflammatory parameters. We did however not observe any apparent effects on tumor formation driven by excessive proliferative signaling downstream from APC-deficiency. Our findings reveal that the role of PACS- 2 in regulating ADAM17-mediated shedding is not an obligate requirement for the epithelium to respond to the strong inflammatory or tumorigenic inducers in the models assessed here.

Original language	English
Journal	OncoTarget
Volume	8
Issue number	65
Pages (from-to)	108303-108315
Number of pages	13
ISSN	1949-2553
DOIs	https://doi.org/10.18632/oncotarget.22661
Publication status	Published - 1 Jan 2017

Keywords

ADAM17
Apc model
Colon cancer
DSS-induced colitis
PACS-2

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Loss of PACS-2 delays regeneration in DSS-induced colitis but does not affect the ApcMin model of colorectal cancerFinal published version, 11.2 MBLicence: CC BY

Cite this

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title = "Loss of PACS-2 delays regeneration in DSS-induced colitis but does not affect the ApcMin model of colorectal cancer",

abstract = "PACS-2 is a multifunctional sorting protein that mediates cell homeostasis. We recently identified PACS-2 in a functional genome-wide siRNA screen for novel regulators of the metalloproteinase ADAM17, the main sheddase for ligands of the ErbB receptor family. Of note, we showed that Pacs2-/- mice have significantly reduced EGFR activity and proliferative index in the intestinal epithelium. As EGFR signaling is highly mitogenic for intestinal epithelial stem cells, and plays essential roles in intestinal epithelial regeneration and tumor development, we have now examined the role of PACS-2 in these processes. Specifically, we analyzed the role of Pacs2- deficiency in a DSS-induced colitis model as well as in the genetic ApcMin colon cancer model. We now report that loss of PACS-2 delays tissue regeneration after colonic injury with little effect on key inflammatory parameters. We did however not observe any apparent effects on tumor formation driven by excessive proliferative signaling downstream from APC-deficiency. Our findings reveal that the role of PACS- 2 in regulating ADAM17-mediated shedding is not an obligate requirement for the epithelium to respond to the strong inflammatory or tumorigenic inducers in the models assessed here.",

keywords = "ADAM17, Apc model, Colon cancer, DSS-induced colitis, PACS-2",

author = "Dombernowsky, {Sarah L.} and Jeanette Schwarz and Jacob Sams{\o}e-Petersen and Reidar Albrechtsen and Jensen, {Kim B.} and Gary Thomas and Marie Kveiborg",

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T1 - Loss of PACS-2 delays regeneration in DSS-induced colitis but does not affect the ApcMin model of colorectal cancer

AU - Dombernowsky, Sarah L.

AU - Schwarz, Jeanette

AU - Samsøe-Petersen, Jacob

AU - Albrechtsen, Reidar

AU - Jensen, Kim B.

AU - Thomas, Gary

AU - Kveiborg, Marie

PY - 2017/1/1

Y1 - 2017/1/1

N2 - PACS-2 is a multifunctional sorting protein that mediates cell homeostasis. We recently identified PACS-2 in a functional genome-wide siRNA screen for novel regulators of the metalloproteinase ADAM17, the main sheddase for ligands of the ErbB receptor family. Of note, we showed that Pacs2-/- mice have significantly reduced EGFR activity and proliferative index in the intestinal epithelium. As EGFR signaling is highly mitogenic for intestinal epithelial stem cells, and plays essential roles in intestinal epithelial regeneration and tumor development, we have now examined the role of PACS-2 in these processes. Specifically, we analyzed the role of Pacs2- deficiency in a DSS-induced colitis model as well as in the genetic ApcMin colon cancer model. We now report that loss of PACS-2 delays tissue regeneration after colonic injury with little effect on key inflammatory parameters. We did however not observe any apparent effects on tumor formation driven by excessive proliferative signaling downstream from APC-deficiency. Our findings reveal that the role of PACS- 2 in regulating ADAM17-mediated shedding is not an obligate requirement for the epithelium to respond to the strong inflammatory or tumorigenic inducers in the models assessed here.

AB - PACS-2 is a multifunctional sorting protein that mediates cell homeostasis. We recently identified PACS-2 in a functional genome-wide siRNA screen for novel regulators of the metalloproteinase ADAM17, the main sheddase for ligands of the ErbB receptor family. Of note, we showed that Pacs2-/- mice have significantly reduced EGFR activity and proliferative index in the intestinal epithelium. As EGFR signaling is highly mitogenic for intestinal epithelial stem cells, and plays essential roles in intestinal epithelial regeneration and tumor development, we have now examined the role of PACS-2 in these processes. Specifically, we analyzed the role of Pacs2- deficiency in a DSS-induced colitis model as well as in the genetic ApcMin colon cancer model. We now report that loss of PACS-2 delays tissue regeneration after colonic injury with little effect on key inflammatory parameters. We did however not observe any apparent effects on tumor formation driven by excessive proliferative signaling downstream from APC-deficiency. Our findings reveal that the role of PACS- 2 in regulating ADAM17-mediated shedding is not an obligate requirement for the epithelium to respond to the strong inflammatory or tumorigenic inducers in the models assessed here.

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