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MCL1 is required for maintenance of intestinal homeostasis and prevention of carcinogenesis in mice.
Gastroenterology 159, 183-199 (2020)
BACKGROUND & AIMS: Intestinal epithelial homeostasis depends on a tightly regulated balance between intestinal epithelial cell (IEC) death and proliferation. While the disruption of several IEC death regulating factors result in intestinal inflammation, the loss of the anti-apoptotic BCL2 family members BCL2 and BCL2L1 has no effect on intestinal homeostasis in mice. We investigated the functions of the antiapoptotic protein MCL1, another member of the BCL2 family, in intestinal homeostasis in mice. METHODS: We generated mice with IECspecific disruption of Mcl1 (Mcl1(Delta IEC) mice) or tamoxifeninducible IEC-specific disruption of Mcl1 (i-Mcl1(Delta IEC) mice); these mice and mice with full-length Mcl1 (controls) were raised under normal or germ-free conditions. Mice were analyzed by endoscopy and for intestinal epithelial barrier permeability. Intestinal tissues were analyzed by histology, in situ hybridization, proliferation assays, and immunoblots. Levels of calprotectin, a marker of intestinal inflammation, were measured in intestinal tissues and feces. RESULTS: Mcl1(Delta IEC) mice spontaneously developed apoptotic enterocolopathy, characterized by increased IEC apoptosis, hyperproliferative crypts, epithelial barrier dysfunction, and chronic inflammation. Loss of MCL1 retained intestinal crypts in a hyperproliferated state and prevented the differentiation of intestinal stem cells. Proliferation of intestinal stem cells in MCL1-deficient mice required WNT signaling and was associated with DNA damage accumulation. By 1 year of age, Mcl1(Delta IEC) mice developed intestinal tumors with morphologic and genetic features of human adenomas and carcinomas. Germ-free housing of Mcl1(Delta IEC) mice reduced markers of microbiotainduced intestinal inflammation but not tumor development. CONCLUSION: The antiapoptotic protein MCL1, a member of the BCL2 family, is required for maintenance of intestinal homeostasis and prevention of carcinogenesis in mice. Loss of MCL1 results in development of intestinal carcinomas, even under germ-free conditions, and therefore does not involve microbe-induced chronic inflammation. Mcl1(Delta IEC) mice might be used to study apoptotic enterocolopathy and inflammatory bowel diseases.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Times Cited
Scopus
Cited By
Cited By
Altmetric
17.373
0.000
6
8
Anmerkungen
Besondere Publikation
Auf Hompepage verbergern
Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Colorectal Carcinoma ; Crc ; Cell Death ; Tumorigenesis; Epithelial-cells; Mouse Models; Cancer; Necroptosis; Apoptosis; Differentiation; Proliferation; Inhibition; Caspase-8; Necrosis
Sprache
englisch
Veröffentlichungsjahr
2020
HGF-Berichtsjahr
2020
ISSN (print) / ISBN
0016-5085
e-ISSN
1528-0012
Zeitschrift
Gastroenterology
Quellenangaben
Band: 159,
Heft: 1,
Seiten: 183-199
Verlag
Elsevier
Verlagsort
1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa
Begutachtungsstatus
Peer reviewed
Institut(e)
Translational Metabolic Oncology (IDC-TMO)
POF Topic(s)
30203 - Molecular Targets and Therapies
Forschungsfeld(er)
Radiation Sciences
PSP-Element(e)
G-501000-001
WOS ID
WOS:000550779600002
Erfassungsdatum
2020-10-13