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Alternative polyadenylation (APA) is a widespread and important mechanism in regulation of gene expression. Dysregulation of the 3' UTR cleavage and polyadenylation represents a common characteristic among many disease states including lung fibrosis. In this study, we investigated the role of mammalian cleavage factor I (CFIm)-mediated APA in regulating the extracellular matrix production in response to mechanical stimuli from stiffened matrix simulating the fibrotic lungs. We found that stiff matrix downregulates expression of CFIm68, CFIm59 and CFIm25 subunits, and promotes APA in favor of the proximal poly(A) site usage in the 3' UTRs of type I collagen (COL1A1) and fibronectin (FN1) in primary human lung fibroblasts. Knockdown and overexpression of each individual CFIm subunit demonstrated that CFIm68 and CFIm25 are indispensable attributes of stiff matrix-induced APA and overproduction of COL1A1, whereas CFIm does not appear to mediate stiffness-regulated FN1 APA. Furthermore, expression of the CFIm subunits is associated with matrix stiffness in vivo in a bleomycin-induced mouse model of pulmonary fibrosis. These data suggest that stiff matrix instigates type I collagen biogenesis by selectively targeting mRNA transcripts for 3' UTR shortening. The current study uncovered a potential mechanism for regulation of the CFIm complex by mechanical cues under fibrotic conditions.
This article was published in the following journal.
Name: JCI insight
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An endopeptidase that is structurally similar to MATRIX METALLOPROTEINASE 2. It degrades GELATIN types I and V; COLLAGEN TYPE IV; and COLLAGEN TYPE V.
A non-fibrillar collagen that forms a network of MICROFIBRILS within the EXTRACELLULAR MATRIX of CONNECTIVE TISSUE. The alpha subunits of collagen type VI assemble into antiparallel, overlapping dimers which then align to form tetramers.
A non-fibrillar collagen found in BASEMENT MEMBRANE. The C-terminal end of the alpha1 chain of collagen type XVIII contains the ENDOSTATIN peptide, which can be released by proteolytic cleavage.
A small leucine-rich proteoglycan that contains 4 KERATAN SULFATE chains within the leucine repeat region. It interacts with COLLAGEN TYPE I and COLLAGEN TYPE II fibrils and may function to control the rate of EXTRACELLULAR MATRIX assembly. It also sequesters TRANSFORMING GROWTH FACTOR BETA in the extracellular matrix.
A fibrillar collagen found widely distributed as a minor component in tissues that contain COLLAGEN TYPE I and COLLAGEN TYPE III. It is a heterotrimeric molecule composed of alpha1(V), alpha2(V) and alpha3(V) subunits. Several forms of collagen type V exist depending upon the composition of the subunits that form the trimer.
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Pulmonary relating to or associated with the lungs eg Asthma, chronic bronchitis, emphysema, COPD, Cystic Fibrosis, Influenza, Lung Cancer, Pneumonia, Pulmonary Arterial Hypertension, Sleep Disorders etc Follow and track Lung Cancer News ...