The mRNA decay promoting factor K-homology splicing regulator protein post-transcriptionally determines parathyroid hormone mRNA levels.
Serum calcium and phosphate concentrations and experimental chronic kidney failure control parathyroid hormone (PTH) gene expression post-transcriptionally through regulated binding of the trans-acting proteins AUF1 and upstream of N-ras (Unr) to an AU-rich element (ARE) in PTH mRNA 3'-untranslated region (3'UTR). We show that the mRNA decay promoting K-homology splicing regulator protein (KSRP) binds to PTH mRNA in intact parathyroid glands and in transfected cells. This binding is decreased in glands from calcium-depleted or experimental chronic kidney failure rats in which PTH mRNA is more stable compared to parathyroid glands from control and phosphorus-depleted rats in which PTH mRNA is less stable. PTH mRNA decay depends on the KSRP-recruited exosome in parathyroid extracts. In transfected cells, KSRP overexpression and knockdown experiments show that KSRP decreases PTH mRNA stability and steady-state levels through the PTH mRNA ARE. Overexpression of isoform p45 of the PTH mRNA stabilizing protein AUF1 blocks KSRP-PTH mRNA binding and partially prevents the KSRP mediated decrease in PTH mRNA levels. Therefore, calcium or phosphorus depletion, as well as chronic kidney failure, regulate the interaction of KSRP and AUF1 with PTH mRNA and its half-life. Our data indicate a novel role for KSRP in PTH gene expression.
Nechama
Morris
M
Minerva Center for Calcium and Bone Metabolism, Hadassah Hebrew University Medical Center, PO Box 12000, Jerusalem, Israel 91120.
Ben-Dov
Iddo Z
IZ
Briata
Paola
P
Gherzi
Roberto
R
Naveh-Many
Tally
T
D020413:3' Untranslated Regions / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002908:Chronic Disease; D005786:Gene Expression Regulation; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism; D008297:Male; D009154:Mutation; D010280:Parathyroid Glands / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000235:genetics*; D010710:Phosphates / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000096:biosynthesis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D020413:3' Untranslated Regions; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; C000630988:Hnrnpd protein, rat; C105789:KHSRP protein, human; D010281:Parathyroid Hormone; D010710:Phosphates; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D002118:Calcium