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van der Meer JHM, de Boer RJ, Meijer BJ, et al. Epithelial argininosuccinate synthetase is dispensable for intestinal regeneration and tumorigenesis. Cell Death Dis. 2021;12(10):897doi: 10.1038/s41419-021-04173-x.
van der Meer, J. H. M., de Boer, R. J., Meijer, B. J., Smit, W. L., Vermeulen, J. L. M., Meisner, S., van Roest, M., Koelink, P. J., Dekker, E., Hakvoort, T. B. M., Koster, J., Hawinkels, L. J. A. C., Heijmans, J., Struijs, E. A., Boermeester, M. A., van den Brink, G. R., & Muncan, V. (2021). Epithelial argininosuccinate synthetase is dispensable for intestinal regeneration and tumorigenesis. Cell death & disease, 12(10), 897. https://doi.org/10.1038/s41419-021-04173-x
van der Meer, Jonathan H M, et al. "Epithelial argininosuccinate synthetase is dispensable for intestinal regeneration and tumorigenesis." Cell death & disease vol. 12,10 (2021): 897. doi: https://doi.org/10.1038/s41419-021-04173-x
van der Meer JHM, de Boer RJ, Meijer BJ, Smit WL, Vermeulen JLM, Meisner S, van Roest M, Koelink PJ, Dekker E, Hakvoort TBM, Koster J, Hawinkels LJAC, Heijmans J, Struijs EA, Boermeester MA, van den Brink GR, Muncan V. Epithelial argininosuccinate synthetase is dispensable for intestinal regeneration and tumorigenesis. Cell Death Dis. 2021 Oct 01;12(10):897. doi: 10.1038/s41419-021-04173-x. PMID: 34599156; PMCID: PMC8486827.
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Cell Death Dis. 2021 Oct 01;12(10):897. doi: 10.1038/s41419-021-04173-x.

Epithelial argininosuccinate synthetase is dispensable for intestinal regeneration and tumorigenesis.

Cell death & disease

Jonathan H M van der Meer, Ruben J de Boer, Bartolomeus J Meijer, Wouter L Smit, Jacqueline L M Vermeulen, Sander Meisner, Manon van Roest, Pim J Koelink, Evelien Dekker, Theodorus B M Hakvoort, Jan Koster, Lukas J A C Hawinkels, Jarom Heijmans, Eduard A Struijs, Marja A Boermeester, Gijs R van den Brink, Vanesa Muncan

Affiliations

  1. Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 69-71, Amsterdam, The Netherlands.
  2. Amsterdam UMC, University of Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 69-71, Amsterdam, The Netherlands.
  3. Amsterdam UMC, University of Amsterdam, Department of Oncogenomics, Cancer Center Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
  4. Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
  5. Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Clinical Chemistry, Amsterdam Gastroenterology Endocrinology Metabolism, de Boelelaan 1117, Amsterdam, The Netherlands.
  6. Amsterdam UMC, University of Amsterdam, Department of Surgery, Meibergdreef 9, Amsterdam, The Netherlands.
  7. Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, Switzerland.
  8. Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 69-71, Amsterdam, The Netherlands. [email protected].

PMID: 34599156 PMCID: PMC8486827 DOI: 10.1038/s41419-021-04173-x

Abstract

The epithelial signaling pathways involved in damage and regeneration, and neoplastic transformation are known to be similar. We noted upregulation of argininosuccinate synthetase (ASS1) in hyperproliferative intestinal epithelium. Since ASS1 leads to de novo synthesis of arginine, an important amino acid for the growth of intestinal epithelial cells, its upregulation can contribute to epithelial proliferation necessary to be sustained during oncogenic transformation and regeneration. Here we investigated the function of ASS1 in the gut epithelium during tissue regeneration and tumorigenesis, using intestinal epithelial conditional Ass1 knockout mice and organoids, and tissue specimens from colorectal cancer patients. We demonstrate that ASS1 is strongly expressed in the regenerating and Apc-mutated intestinal epithelium. Furthermore, we observe an arrest in amino acid flux of the urea cycle, which leads to an accumulation of intracellular arginine. However, loss of epithelial Ass1 does not lead to a reduction in proliferation or increase in apoptosis in vivo, also in mice fed an arginine-free diet. Epithelial loss of Ass1 seems to be compensated by altered arginine metabolism in other cell types and the liver.

© 2021. The Author(s).

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