title: Repeated H2 O2 exposure drives cell cycle progression in an in vitro model of ulcerative colitis.
abstract: The production of hydrogen peroxide (H2 O2 ) drives tumourigenesis in ulcerative colitis (UC). Recently, we showed that H2 O2 activates DNA damage checkpoints in human colonic epithelial cells (HCEC) through c-Jun N-terminal Kinases (JNK) that induces p21(WAF1) . Moreover, caspases circumvented the G1/S and intra-S checkpoints, and cells accumulated in G2/M. The latter observation raised the question of whether repeated H2 O2 exposures alter JNK activation, thereby promoting a direct passage of cells from G2/M arrest to driven cell cycle progression. Here, we report that increased proliferation of repeatedly H2 O2 -exposed HCEC cells (C-cell cultures) was associated with (i) increased phospho-p46 JNK, (ii) decreased total JNK and phospho-p54 JNK and (iii) p21(WAF1) down-regulation. Altered JNK activation and p21(WAF1) down-regulation were accompanied by defects in maintaining G2/M and mitotic spindle checkpoints through adaptation, as well as by apoptosis resistance following H2 O2 exposure. This may cause increased proliferation of C-cell cultures, a defining initiating feature in the inflammation-carcinoma pathway in UC. We further suggest that dysregulated JNK activation is attributed to a non-apoptotic function of caspases, causing checkpoint adaptation in C-cell cultures. Additionally, loss of cell-contact inhibition and the overcoming of senescence, hallmarks of cancer, contributed to increased proliferation. Furthermore, there was evidence that p54 JNK inactivation is responsible for loss of cell-contact inhibition. We present a cellular model of UC and suggest a sinusoidal pattern of proliferation, which is triggered by H2 O2 -induced reactive oxygen species generation, involving an interplay between JNK activation/inactivation, p21(WAF1) , c-Fos, c-Jun/phospho-c-Jun, ATF2/phospho-ATF2, β-catenin/TCF4-signalling, c-Myc, CDK6 and Cyclin D2, leading to driven cell cycle progression.
authors.affiliation: Department of Pathology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Poehlmann
authors.forename: Kathrin
authors.initials: K
authors.lastname: Reissig
authors.forename: Peter
authors.initials: P
authors.lastname: Schönfeld
authors.forename: Diana
authors.initials: D
authors.lastname: Walluscheck
authors.forename: Antje
authors.initials: A
authors.lastname: Schinlauer
authors.forename: Roland
authors.initials: R
authors.lastname: Hartig
authors.forename: Wiebke
authors.initials: W
authors.lastname: Lessel
authors.forename: Thomas
authors.initials: T
authors.lastname: Guenther
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
authors.forename: Albert
authors.initials: A
authors.lastname: Roessner
mesh_terms: D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003093:Colitis, Ulcerative / Q000473:pathology*; D003260:Contact Inhibition / Q000187:drug effects; D056742:Cyclin D2 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D056742:Cyclin D2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D006861:Hydrogen Peroxide; D051361:Cyclin-Dependent Kinase 6; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases
keywords: DNA damage checkpoint adaptation; cell cycle progression; hydrogen peroxide; ulcerative colitis