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Competition between RNA-binding proteins CELF1 and HuR modulates MYC translation
and intestinal epithelium renewal
#MMPMID25808495
Liu L
; Ouyang M
; Rao JN
; Zou T
; Xiao L
; Chung HK
; Wu J
; Donahue JM
; Gorospe M
; Wang JY
Mol Biol Cell
2015[May]; 26
(10
): 1797-810
PMID25808495
show ga
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.
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