title: Competition between RNA-binding proteins CELF1 and HuR modulates MYC translation and intestinal epithelium renewal.
abstract: The mammalian intestinal epithelium is one of the most rapidly self-renewing tissues in the body, and its integrity is preserved through strict regulation. The RNA-binding protein (RBP) ELAV-like family member 1 (CELF1), also referred to as CUG-binding protein 1 (CUGBP1), regulates the stability and translation of target mRNAs and is implicated in many aspects of cellular physiology. We show that CELF1 competes with the RBP HuR to modulate MYC translation and regulates intestinal epithelial homeostasis. Growth inhibition of the small intestinal mucosa by fasting in mice was associated with increased CELF1/Myc mRNA association and decreased MYC expression. At the molecular level, CELF1 was found to bind the 3'-untranslated region (UTR) of Myc mRNA and repressed MYC translation without affecting total Myc mRNA levels. HuR interacted with the same Myc 3'-UTR element, and increasing the levels of HuR decreased CELF1 binding to Myc mRNA. In contrast, increasing the concentrations of CELF1 inhibited formation of the [HuR/Myc mRNA] complex. Depletion of cellular polyamines also increased CELF1 and enhanced CELF1 association with Myc mRNA, thus suppressing MYC translation. Moreover, ectopic CELF1 overexpression caused G1-phase growth arrest, whereas CELF1 silencing promoted cell proliferation. These results indicate that CELF1 represses MYC translation by decreasing Myc mRNA association with HuR and provide new insight into the molecular functions of RBPs in the regulation of intestinal mucosal growth.
authors: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201.
authors: Lan
authors: L
authors: Liu
authors: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201.
authors: Miao
authors: M
authors: Ouyang
authors: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201.
authors: Jaladanki N
authors: JN
authors: Rao
authors: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201.
authors: Tongtong
authors: T
authors: Zou
authors: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201.
authors: Lan
authors: L
authors: Xiao
authors: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201.
authors: Hee Kyoung
authors: HK
authors: Chung
authors: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201.
authors: Jing
authors: J
authors: Wu
authors: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201.
authors: James M
authors: JM
authors: Donahue
authors: Laboratory of Genetics and Genomics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224.
authors: Myriam
authors: M
authors: Gorospe
authors: Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201 Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201 Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201 jwang@smail.umaryland.edu.
authors: Jian-Ying
authors: JY
authors: Wang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001667:Binding, Competitive; D000067879:CELF1 Protein / Q000378:metabolism*; D002460:Cell Line; D000066673:Cell Self Renewal; D000067780:ELAV-Like Protein 1 / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014176:Protein Biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats
chemical_list: D020413:3' Untranslated Regions; D000067879:CELF1 Protein; D000067780:ELAV-Like Protein 1; D016271:Proto-Oncogene Proteins c-myc