Role of nucleolin in posttranscriptional control of MMP-9 expression.
Matrix-metalloproteinases (MMPs), which are able to degrade extra cellular matrix (ECM) components, are crucial in ECM-remodeling, under physiological (e.g., embryogenesis, wound healing, angiogenesis) or pathophysiological conditions (e.g., arthritis, cancer progression and metastasis, fibrosis). Treating HT1080 cells, a human fibrosarcoma cell line, with the iron chelator 2,2-Dipyridyl, which mimics certain aspects of hypoxia, leads to a 3-fold elevated Matrix-metalloproteinase-9 (MMP-9) protein level. This elevation occurs within 3 h, without any change of mRNA-concentration. The rapid increase in MMP-9 expression is caused by an enhancement of translational efficiency characterized by a recruitment of translationally inactive MMP-9 mRNP-complexes into the rough endoplasmatic reticulum (rER). Reporter gene assays, which depend on the untranslated regions (UTR) of MMP-9 mRNA, reveal that the posttranscriptional regulation is mainly attributed to the 3'UTR. RNA/protein interaction studies indicate that the elevated binding of nucleolin ( approximately 64 kDa form) to the 3'UTR may be of major importance for the increased efficiency of MMP-9 translation. The results show that MMP-9 expression can be regulated posttranscriptionally, affecting the efficiency of translation and localization of the mRNA.
Fähling
Michael
M
Charité, Universitätsmedizin Berlin, Institut für Vegetative Physiologie, 10117 Berlin, Germany. Michael.Faehling@charite.de
Steege
Andreas
A
Perlewitz
Andrea
A
Nafz
Benno
B
Mrowka
Ralf
R
Persson
Pontus B
PB
Thiele
Bernd J
BJ
D015082:2,2'-Dipyridyl / Q000494:pharmacology; D020413:3' Untranslated Regions / Q000502:physiology*; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D005354:Fibrosarcoma; D005786:Gene Expression Regulation; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D010750:Phosphoproteins / Q000502:physiology*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000502:physiology*; D000097796:Nucleolin
D015082:2,2'-Dipyridyl; D020413:3' Untranslated Regions; D003513:Cycloheximide; D020780:Matrix Metalloproteinase 9; D010750:Phosphoproteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000097796:Nucleolin