galectin-3 mediates cross-talk between k-ras and let-7c tumor suppressor micrornagalectin-3调和k - ras基因之间的相声和let-7c肿瘤抑制微rna.pdfVIP

Galectin-3 Mediates Cross-Talk between K-Ras and Let-7c Tumor Suppressor microRNA 1 1 2 3 1 Ran Levy , Anat Biran , Francoise Poirier , Avraham Raz , Yoel Kloog * ´ 1 Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel, 2 Institut Jacques Monod Institute, Universite Paris Diderot/ CNRS, Paris CEDEX 13, France, 3 Department of Oncology and Pathology, School of Medicine, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, United States of America Abstract Background: Galectin-3 (Gal-3) and active (GTP-bound) K-Ras contribute to the malignant phenotype of many human tumors by increasing the rate of cell proliferation, survival, and migration. These Gal-3-mediated effects result from a selective binding to K-Ras.GTP, causing increased nanoclustering in the cell membrane and leading to robust Ras signaling. Regulation of the interactions between Gal-3 and active K-Ras is not fully understood. Methods and Findings: To gain a better understanding of what regulates the critical interactions between these two proteins, we examined the role of Gal-3 in the regulation of K-Ras by using Gal-3-knockout mouse embryonic-fibroblasts (Gal-3-/- MEFs) and/or Gal-3/Gal-1 double-knockout MEFs. We found that knockout of Gal-3 induced strong downregulation (,60%) of K-Ras and K-Ras.GTP. The downregulation was somewhat more marked in the double-knockout MEFs, in which we also detected robust inhibition(,50%) of ERK and Akt activation. These additional effects are probably attributable to inhibition of the weak interactions of K-Ras.GTP with