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LC3-mediated fibronectin mRNA translation induces fibrosarcoma growth by increasing connective tissue growth factor.

Authors: Ying, L  Lau, A  Alvira, CM  West, R  Cann, GM  Zhou, B  Kinnear, C  Jan, E  Sarnow, P  Van de Rijn, M  Rabinovitch, M 
Citation: Ying L, etal., J Cell Sci. 2009 May 1;122(Pt 9):1441-51. Epub 2009 Apr 14.
Pubmed: (View Article at PubMed) PMID:19366727
DOI: Full-text: DOI:10.1242/jcs.025957

Previously, we related fibronectin (Fn1) mRNA translation to an interaction between an AU-rich element in the Fn1 3' UTR and light chain 3 (LC3) of microtubule-associated proteins 1A and 1B. Since human fibrosarcoma (HT1080) cells produce little fibronectin and LC3, we used these cells to investigate how LC3-mediated Fn1 mRNA translation might alter tumor growth. Transfection of HT1080 cells with LC3 enhanced fibronectin mRNA translation. Using polysome analysis and RNA-binding assays, we show that elevated levels of translation depend on an interaction between a triple arginine motif in LC3 and the AU-rich element in Fn1 mRNA. Wild-type but not mutant LC3 accelerated HT1080 cell growth in culture and when implanted in SCID mice. Comparison of WT LC3 with vector-transfected HT1080 cells revealed increased fibronectin-dependent proliferation, adhesion and invasion. Microarray analysis of genes differentially expressed in WT and vector-transfected control cells indicated enhanced expression of connective tissue growth factor (CTGF). Using siRNA, we show that enhanced expression of CTGF is fibronectin dependent and that LC3-mediated adhesion, invasion and proliferation are CTGF dependent. Expression profiling of soft tissue tumors revealed increased expression of both LC3 and CTGF in some locally invasive tumor types.

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CRRD Object Information
CRRD ID: 2314525
Created: 2009-11-19
Species: All species
Last Modified: 2009-11-19
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.