title: The Myb-p300-CREB axis modulates intestine homeostasis, radiosensitivity and tumorigenesis.
abstract: The gastrointestinal (GI) epithelium is constantly renewing, depending upon the intestinal stem cells (ISC) regulated by a spectrum of transcription factors (TFs), including Myb. We noted previously in mice with a p300 mutation (plt6) within the Myb-interaction-domain phenocopied Myb hypomorphic mutant mice with regard to thrombopoiesis, and here, changes in GI homeostasis. p300 is a transcriptional coactivator for many TFs, most prominently cyclic-AMP response element-binding protein (CREB), and also Myb. Studies have highlighted the importance of CREB in proliferation and radiosensitivity, but not in the GI. This prompted us to directly investigate the p300-Myb-CREB axis in the GI. Here, the role of CREB has been defined by generating GI-specific inducible creb knockout (KO) mice. KO mice show efficient and specific deletion of CREB, with no evident compensation by CREM and ATF1. Despite complete KO, only modest effects on proliferation, radiosensitivity and differentiation in the GI under homeostatic or stress conditions were evident, even though CREB target gene pcna (proliferating cell nuclear antigen) was downregulated. creb and p300 mutant lines show increased goblet cells, whereas a reduction in enteroendocrine cells was apparent only in the p300 line, further resembling the Myb hypomorphs. When propagated in vitro, crebKO ISC were defective in organoid formation, suggesting that the GI stroma compensates for CREB loss in vivo, unlike in MybKO studies. Thus, it appears that p300 regulates GI differentiation primarily through Myb, rather than CREB. Finally, active pCREB is elevated in colorectal cancer (CRC) cells and adenomas, and is required for the expression of drug transporter, MRP2, associated with resistance to Oxaliplatin as well as several chromatin cohesion protein that are relevant to CRC therapy. These data raise the prospect that CREB may have a role in GI malignancy as it does in other cancer types, but unlike Myb, is not critical for GI homeostasis.
authors.affiliation: Differentiation and Transcription Laboratory, Peter MacCallum Cancer Center,East Melbourne, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Sampurno
authors.forename: A
authors.initials: A
authors.lastname: Bijenhof
authors.forename: D
authors.initials: D
authors.lastname: Cheasley
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.forename: S
authors.initials: S
authors.lastname: Robine
authors.forename: D
authors.initials: D
authors.lastname: Hilton
authors.forename: W S
authors.initials: WS
authors.lastname: Alexander
authors.forename: L
authors.initials: L
authors.lastname: Pereira
authors.forename: T
authors.initials: T
authors.lastname: Mantamadiotis
authors.forename: J
authors.initials: J
authors.lastname: Malaterre
authors.forename: R G
authors.initials: RG
authors.lastname: Ramsay
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009154:Mutation; D009940:Organoids / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance; D016415:Sequence Alignment; D014916:Whole-Body Irradiation; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D018809:Proliferating Cell Nuclear Antigen; D011506:Proteins; D020598:Proto-Oncogene Proteins c-myb; D050880:p300-CBP Transcription Factors; C079238:alcohol O-acetyltransferase