Role of HuR in Skeletal Myogenesis through Coordinate Regulation of Muscle Differentiation Genes

Abstract

In this report, we investigate the role of the RNA-binding protein HuR during skeletal myogenesis. At the onset of myogenesis in differentiating C2C12 myocytes and in vivo in regenerating mouse muscle, HuR cytoplasmic abundance increased dramatically, returning to a predominantly nuclear presence upon completion of myogenesis. mRNAs encoding key regulators of myogenesis-specific transcription (myogenin and MyoD) and cell cycle withdrawal (p21), bearing AU-rich regions, were found to be targets of HuR in a differentiationdependent manner. Accordingly, mRNA half-lives were highest during differentiation, declining when differentiation was completed. Importantly, HuR-overexpressing C2C12 cells displayed increased target mRNA expression and half-life and underwent precocious differentiation. Our findings underscore a critical function for HuR during skeletal myogenesis linked to HuR's coordinate regulation of muscle differentiation genes.

Mechanisms of regulatory diversity within the p53 transcriptional network

“…Reports from outside the p53 field reveal the importance of post-transcriptional regulation of the p21 waf1 gene in several biological processes such as tissue differentiation. A number of cis-regulatory elements present in the 3 0 -UTR of the p21 waf1 mRNA have been identified, as well as RNA-binding proteins recognizing these sequences (Johannessen et al, 1999;Figueroa et al, 2003;Lal et al, 2004;Yang et al, 2004;Shi et al, 2005). Recently, the Chen group identified a novel p53 target gene, named RNPC1, which codes for an RNA-binding protein capable of stabilizing p21 waf1 mRNA (Shu et al, 2006).…”

Overexpression of the RNA binding protein HuR impairs tumor growth in triple negative breast cancer associated with deficient angiogenesis

“…[37][38][39] Published reports from our lab and others demonstrate that HuR critically regulates myogenesis by controlling the expression of three central genes in this process. 40,41 HuR siRNA knock down prevents muscle formation, whereas HuR overexpression results in precocious differentiation. 40,41 Yet, it is highly likely HuR is interacting with many more targets inside these cells.…”

“…40,41 HuR siRNA knock down prevents muscle formation, whereas HuR overexpression results in precocious differentiation. 40,41 Yet, it is highly likely HuR is interacting with many more targets inside these cells. The exact explanations for this discrete phenotype are not presently understood.…”

PI3K/AKT signaling determines a dynamic switch between distinct KSRP functions favoring skeletal myogenesis

“…4 In the recent few years, extensive analysis of the composition of the transcriptome assembled on the chromatin of myogenic loci has been performed (reviewed in Guasconi and Puri 5 ), although knowledge on the mechanisms that post-transcriptionally regulate muscle differentiation and regeneration is more limited. [6][7][8][9] Recently, genetic, and biological evidence of an essential role of microRNAs (miRNAs) in muscle development and function has been accumulating and a group of miRNAs, highly enriched in skeletal muscle (referred to as myomiRs), has been identified (reviewed in Williams et al, 10 and Gü ller and Russell 11 ). MyomiRs influence multiple aspects of muscle development and function through their regulation of key genes controlling myogenesis.…”