No abstract

A high expression level of the ␤-actin protein is required for important biological mechanisms, such as maintaining cell shape, growth, and motility. Although the elevated cellular level of the ␤-actin protein is directly linked to the long half-life of its mRNA, the molecular mechanisms responsible for this effect are unknown. Here we show that the RNA-binding protein HuR stabilizes the ␤-actin mRNA by associating with a uridine-rich element within its 3 untranslated region. Using RNA interference to knock down the expression of HuR in HeLa cells, we demonstrate that HuR plays an important role in the stabilization but not in the nuclear/cytoplasmic distribution of the ␤-actin mRNA. HuR depletion in HeLa cells alters key ␤-actin-based cytoskeleton functions, such as cell adhesion, migration, and invasion, and these defects correlate with a loss of the actin stress fiber network. Together our data establish that the posttranscriptional event involving HuR-mediated ␤-actin mRNA stabilization could be a part of the regulatory mechanisms responsible for maintaining cell integrity, which is a prerequisite for avoiding transformation and tumor formation.

Renal cell carcinomas (RCC) are emerging as a complex set of diseases with major socioeconomic impact and a continued rise in incidence throughout the world. As the field of urologic oncology faces these trends, several major genomic and mechanistic discoveries have altered our core understanding of this multitude of cancers, including several new rare subtypes of renal cancers. This review will examine these new findings, and place them in the context of the well-established association of clear cell RCC (ccRCC) with mutations in the von Hippel-Lindau (VHL) gene and resultant aberrant hypoxia inducible factor (HIF) signaling. The impact of novel ccRCC-associated genetic lesions on chromatin remodeling and epigenetic regulation is explored. The effects of VHL mutation on primary ciliary function, extracellular matrix homeostasis, and tumor metabolism are discussed. VHL proteostasis is reviewed, with the goal of harnessing the proteostatic machinery to refunctionalize mutant VHL. Translational efforts using molecular tools to understand discriminating features of ccRCC tumors and develop improved prognostic and predictive algorithms are presented and new therapeutics arising from the earliest molecular discoveries in ccRCC are summarized. By creating an integrated review of the key genomic and molecular biological disease characteristics of ccRCC and placing these data in the context of the evolving therapeutic landscape, we intend to facilitate interaction between basic, translational and clinical researchers involved in the treatment of this devastating disease, and accelerate progress towards its ultimate eradication.