title: TIGAR is required for efficient intestinal regeneration and tumorigenesis.
abstract: Regulation of metabolic pathways plays an important role in controlling cell growth, proliferation, and survival. TIGAR acts as a fructose-2,6-bisphosphatase, potentially promoting the pentose phosphate pathway to produce NADPH for antioxidant function and ribose-5-phosphate for nucleotide synthesis. The functions of TIGAR were dispensable for normal growth and development in mice but played a key role in allowing intestinal regeneration in vivo and in ex vivo cultures, where growth defects due to lack of TIGAR were rescued by ROS scavengers and nucleosides. In a mouse intestinal adenoma model, TIGAR deficiency decreased tumor burden and increased survival, while elevated expression of TIGAR in human colon tumors suggested that deregulated TIGAR supports cancer progression. Our study demonstrates the importance of TIGAR in regulating metabolism for regeneration and cancer development and identifies TIGAR as a potential therapeutic target in diseases such as ulcerative colitis and intestinal cancer.
authors.affiliation: CR-UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Cheung
authors.forename: Dimitris
authors.initials: D
authors.lastname: Athineos
authors.forename: Pearl
authors.initials: P
authors.lastname: Lee
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Ridgway
authors.forename: Wendy
authors.initials: W
authors.lastname: Lambie
authors.forename: Colin
authors.initials: C
authors.lastname: Nixon
authors.forename: Douglas
authors.initials: D
authors.lastname: Strathdee
authors.forename: Karen
authors.initials: K
authors.lastname: Blyth
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Karen H
authors.initials: KH
authors.lastname: Vousden
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007414:Intestinal Neoplasms / Q000378:metabolism / Q000473:pathology*; D007422:Intestines / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010744:Phosphoric Monoester Hydrolases; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012038:Regeneration; D013997:Time Factors
chemical_list: D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human; C554952:TIGAR protein, mouse