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.

Quinaldic acid inhibits proliferation of colon cancer HT-29 cells in vitro: Effects on signaling pathways

“…Although we did not confirm any stimulatory effect of quinaldic acid on HT-29 cell proliferation, previous work reported that active p-CREB is elevated in colorectal cancer cells, which suggests that CREB may have a role in gastrointestinal malignancy (Sampurno et al, 2013). Moreover, CREB overexpression may lead to drug resistance of colon cancer cells as it is required for the expression of MRP2 (multidrug resistant protein 2) (Sampurno et al, 2013).…”

A Role for cAMP and Protein Kinase A in Experimental Necrotizing Enterocolitis

“…CREB has been found in phosphorylated states in gastrointestinal malignancy; however, its role in intestinal homeostasis remains unclear. 72 In our experimental models cAMP elevation precedes CREB phosphorylation, as would be expected. However, the initial peak of pCREB precedes that of pPKA, suggesting an alternative mechanism of CREB activation.…”

Coordinated induction of GST and MRP2 by cAMP in Caco-2 cells: Role of protein kinase A signaling pathway and toxicological relevance

“…Recently, Sampurno et al (2013) demonstrated that in mouse colorectal cancer (CRC) cells and adenomas, pCREB is elevated and is required for the increased expression of Mrp2. This was tentatively associated with increased chemoresistance to frontline drugs such as oxaliplatin, 5-fluorouracil, and camptothecin.…”