KSRP-PMR1-exosome association determines parathyroid hormone mRNA levels and stability in transfected cells
1 Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
2 Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY, USA
3 Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
4 Department of Molecular & Cellular Biochemistry, The Ohio State University, Columbus, Ohio, USA
BMC Cell Biology 2009, 10:70 doi:10.1186/1471-2121-10-70Published: 23 September 2009
Parathyroid hormone (PTH) gene expression is regulated post-transcriptionally through the binding of the trans-acting proteins AU rich binding factor 1 (AUF1), Upstream of N-ras (Unr) and KH-type splicing regulatory protein (KSRP) to an AU rich element (ARE) in PTH mRNA 3'-UTR. AUF1 and Unr stabilize PTH mRNA while KSRP, recruiting the exoribonucleolytic complex exosome, promotes PTH mRNA decay.
PTH mRNA is cleaved by the endoribonuclease polysomal ribonuclease 1 (PMR1) in an ARE-dependent manner. Moreover, PMR1 co-immunoprecipitates with PTH mRNA, the exosome and KSRP. Knock-down of either exosome components or KSRP by siRNAs prevents PMR1-mediated cleavage of PTH mRNA.
PTH mRNA is a target for the endonuclease PMR1. The PMR1 mediated decrease in PTH mRNA levels involves the PTH mRNA 3'-UTR ARE, KSRP and the exosome. This represents an unanticipated mechanism by which the decay of an ARE-containing mRNA is facilitated by KSRP and is dependent on both the exosome and an endoribonuclease.