Fibroblast growth factor 1 induced during myogenesis by a transcription–translation coupling mechanism

Abstract

Fibroblast growth factor 1 (FGF1) is involved in muscle development and regeneration. The FGF1 gene contains four tissue-specific promoters allowing synthesis of four transcripts with distinct leader regions. Two of these transcripts contain internal ribosome entry sites (IRESs), which are RNA elements allowing mRNA translation to occur in conditions of blockade of the classical cap-dependent mechanism. Here, we investigated the function and the regulation of FGF1 during muscle differentiation and regeneration. Our data show that FGF1 protein expression is induced in differentiating myoblasts and regenerating mouse muscle, whereas siRNA knock-down demonstrated FGF1 requirement for myoblast differentiation. FGF1 induction occurred at both transcriptional and translational levels, involving specific activation of both promoter A and IRES A, whereas global cap-dependent translation was inhibited. Furthermore, we identified, in the FGF1 promoter A distal region, a cis-acting element able to activate the IRES A-driven translation. These data revealed a mechanism of molecular coupling of mRNA transcription and translation, involving a unique process of IRES activation by a promoter element. The crucial role of FGF1 in myoblast differentiation provides physiological relevance to this novel mechanism. This finding also provides a new insight into the molecular mechanisms linking different levels of gene expression regulation.

The methyl-CpG-binding protein CIBZ suppresses myogenic differentiation by directly inhibiting myogenin expression

“…As shown in Figure 1B, treatment with CTX in skel- etal muscle induced regeneration on day 3, evidenced by the up-regulation of Myog at both the mRNA and protein levels. These observations confirm previous reports [24,25]. Conversely, CIBZ protein was down-regulated on days 1 and 3 post-injection, whereas CIBZ mRNA levels did not change appreciably.…”

1,25(OH)2vitamin D3 enhances myogenic differentiation by modulating the expression of key angiogenic growth factors and angiogenic inhibitors in C2C12 skeletal muscle cells

“…The increase expression of FGF-1 induced by 1,25D-3 agrees with the concept that FGF-1 up-regulation is required for myoblast differentiation since FGF-1 knock-down by siRNA attenuates Myogenin induction originating in abnormal myotubes [16]. Moreover, it has been shown that FGF-1 is expressed in dystrophic muscle, suggesting a positive role in the regeneration of skeletal muscle fibers [36, 37].…”

“…Fibroblast growth factor-1 (FGF-1), a member of the heparin-binding growth factor family and a well-known pro-angiogenic factor, is induced during myogenesis and is required during myoblast differentiation [16]. Vascular endothelial growth factor alpha (VEGFa) another key inducer of angiogenesis, is regulated as part of the myogenic differentiation program and regulates myogenesis in an autocrine function [17].…”

The translational repressor 4E-BP mediates the hypoxia-induced defects in myotome cells

“…Interestingly, IRES have been identified in several mammalian mRNAs, mainly in control genes such as transcription factors and growth factors (Vagner et al, 2001). For instance, functional IRESs have been recently identified in Fibroblast Growth Factor 1 (Martineau et al, 2004;Conte et al, 2009), which plays a crucial role in myoblast differentiation. It is noteworthy that a number of genes including the hypoxiainducible genes encoding HIF-1a remain preferentially translated when eIF4E is sequestered by its repressor 4E-BP (Wouters and Koritzinsky, 2008) and we show that HIF-1a mRNA levels increased depending on the oxygen availability.…”