Translational repression of human matrix metalloproteinases-13 by an alternatively spliced form of T-cell-restricted intracellular antigen-related protein (TIAR).
Human matrix metalloproteinases-13 (HMMP13) shows a wide substrate specificity, and its expression is limited to pathological situations such as chronic inflammation and cancer. The coding sequence for HMMP13 is 86% identical to rat matrix metalloproteinases-13 (RMMP13); however, the regulation of HMMP13 and RMMP13 protein synthesis in renal mesangial cells is strikingly different. In human cells there is a discordance between HMMP13 mRNA levels and protein expression. Following IL-1 beta or TGF-beta(1) stimulation, HMMP13 mRNA levels increase significantly, whereas the protein expression is absent. This discordance is because of a species-dependent translational repression. In addition to the 3'-untranslated region of the matrix metalloproteinases-13 (MMP13) gene, the differential expression of an alternatively spliced transcript of the RNA-binding protein TIAR in human cell cultures is also critical for this post-transcriptional regulation. Transient expression of the 17-amino acid insert of the alternatively spliced form of TIAR reverses the HMMP13 mRNA silencing observed in human and primate species. In addition, co-transfection of the alternatively spliced form of TIAR and HMMP13 into Rat2 cells suppresses HMMP13 protein expression. Thus, we report for the first time that a species-dependent TIAR isoform plays a major role in the post-transcriptional silencing for HMMP13.
Yu
Qing
Q
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Cok
Steven J
SJ
Zeng
Chenbo
C
Morrison
Aubrey R
AR
D020413:3' Untranslated Regions; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D020868:Gene Silencing; D005920:Glomerular Mesangium / Q000166:cytology / Q000201:enzymology; D006801:Humans; D053509:Matrix Metalloproteinase 13; D014176:Protein Biosynthesis / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D051381:Rats
D020413:3' Untranslated Regions; D017931:DNA Primers; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C489666:Tial1 protein, rat; C076751:TIAL1 protein, human; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat