Hana Cho1,2, Ok Hyun Park1, Joori Park, Incheol Ryu, Jeonghan Kim, Jesang Ko, and Yoon Ki Kim3
Division of Life Sciences, Korea University, Seoul 136-701, Republic of Korea
Glucocorticoid receptor (GR), which was originally known to function as a nuclear receptor, plays a role in rapid mRNA degradation by acting as an RNA-binding protein. The mechanism by which this process occurs remains unknown. Here, we demonstrate that GR, preloaded onto the 5′UTR of a target mRNA, recruits UPF1 through proline-rich nuclear receptor coregulatory protein 2 (PNRC2) in a ligand-dependent manner, so as to elicit rapid mRNA degradation. We call this process GR-mediated mRNA decay (GMD). Although GMD, nonsense-mediated mRNA decay (NMD), and staufen-mediated mRNA decay (SMD) share upstream frameshift 1 (UPF1) and PNRC2, we find that GMD is mechanistically distinct from NMD and SMD. We also identify de novo cellular GMD substrates using microarray analysis. Intriguingly, GMD functions in the chemotaxis of human monocytes by targeting chemokine (C-C motif) ligand 2 (CCL2) mRNA. Thus, our data provide molecular evidence of a posttranscriptional role of the well-studied nuclear hormone receptor, GR, which is traditionally considered a transcription factor.
glucocorticoid receptor, PNRC2, UPF1, glucocorticoid receptor-mediated mRNA decay, Nonsense-mediated mRNA decay
1H.C. and O.H.P. contributed equally to this work.
2Present address: Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642.
3To whom correspondence should be addressed.
Author contributions: H.C., O.H.P., J.P., I.R., J. Kim, J. Ko, and Y.K.K. designed research; H.C., O.H.P., J.P., I.R., and J. Kim performed research; H.C., O.H.P., J.P., I.R., and Y.K.K. analyzed data; and H.C., O.H.P., J. Ko, and Y.K.K. wrote the paper.