1. Caspase-mediated Cleavage of RNA-binding Protein HuR Regulates c-Myc Protein Expression after Hypoxic Stress.
- Author
-
Talwar, Sudha, Junfei Jin, Carroll, Brittany, Liu, Angen, Gillespie, Marion Boyd, and Palanisamy, Viswanathan
- Subjects
- *
RNA physiology , *MESSENGER RNA , *PROTEIN synthesis , *GENE expression , *GENETIC regulation , *PROTEIN binding , *PHYSIOLOGY - Abstract
Altered expression of RNA-binding proteins modulates gene expression in association with mRNAs encoding many proto-oncogenes, cytokines, chemokines, and proinflammatory factors. Hu antigen R (HuR), a ubiquitously expressed protein, controls a range of cellular functions such as tumor progression, apoptosis, invasion, and metastasis by stabilizing the AU-rich element located at the 3′-untranslated region (UTR) of target mRNAs. Although significant progress has been made in understanding HuR regulation in gene expression, little is known about how HuR undergoes post-translational modifications and recruits target mRNAs during hypoxic stress. Here, we report that during CoCl2-induced hypoxic stress, HuR is significantly overexpressed and undergoes caspase-dependent cleavage in head and neck squamous cell carcinoma cells. Unexpectedly, the HuR-cleavage product 1 (HuR-CP1) was found to strongly associate with the 3′-UTR of c-myc mRNA and block mRNA translation. The binding efficiency of HuR to the 3′-UTR of c-myc mRNA was confirmed using ribonucleoprotein immunoprecipitation and site-directed mutagenesis at the AU-rich element sequences of the c-myc mRNA. Overexpression of a non-cleavable isoform, HuR-D226A, revealed a potent dominant-negative effect, repressing cleavage of endogenous HuR and promoting cell viability. Surprisingly, under hypoxia, siRNA knockdown of HuR elevated c-Myc protein expression. These findings suggest an important role for HuR in hypoxia, and we may have revealed a novel post-transcriptional mechanism that controls c-Myc expression in oral cancer progression. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF