Galectin-3 mediates cross-talk between K-Ras and Let-7c tumor suppressor microRNA.
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 me...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3216962?pdf=render |
| _version_ | 1811225034581082112 |
|---|---|
| author | Ran Levy Anat Biran Francoise Poirier Avraham Raz Yoel Kloog |
| author_facet | Ran Levy Anat Biran Francoise Poirier Avraham Raz Yoel Kloog |
| author_sort | Ran Levy |
| collection | DOAJ |
| description | 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.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 Gal-1. Re-expression of Gal-3 reversed the phenotype of the Gal-3-/- MEFs and dramatically reduced the disappearance of K-Ras in the presence of cycloheximide to the levels seen in wild-type MEFs. Furthermore, phosphorylation of Gal-3 by casein kinase-1 (CK-1) induced translocation of Gal-3 from the nucleus to the cytoplasm and the plasma membrane, leading to K-Ras stabilization accompanied by downregulation of the tumor suppressor miRNA let-7c, known to negatively control K-Ras transcription.Our results suggest a novel cross-talk between Gal-3-mediated downregulation of let 7c microRNA (which in turn negatively regulates K-Ras transcription) and elucidates the association among Gal-3 let-7c and K-Ras transcription/translation, cellular compartmentalization and activity. |
| first_indexed | 2024-04-12T08:59:00Z |
| format | Article |
| id | doaj.art-1e1de31198c14c4f97d8af92f14eeb40 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T08:59:00Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-1e1de31198c14c4f97d8af92f14eeb402022-12-22T03:39:17ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-01611e2749010.1371/journal.pone.0027490Galectin-3 mediates cross-talk between K-Ras and Let-7c tumor suppressor microRNA.Ran LevyAnat BiranFrancoise PoirierAvraham RazYoel KloogGalectin-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.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 Gal-1. Re-expression of Gal-3 reversed the phenotype of the Gal-3-/- MEFs and dramatically reduced the disappearance of K-Ras in the presence of cycloheximide to the levels seen in wild-type MEFs. Furthermore, phosphorylation of Gal-3 by casein kinase-1 (CK-1) induced translocation of Gal-3 from the nucleus to the cytoplasm and the plasma membrane, leading to K-Ras stabilization accompanied by downregulation of the tumor suppressor miRNA let-7c, known to negatively control K-Ras transcription.Our results suggest a novel cross-talk between Gal-3-mediated downregulation of let 7c microRNA (which in turn negatively regulates K-Ras transcription) and elucidates the association among Gal-3 let-7c and K-Ras transcription/translation, cellular compartmentalization and activity.http://europepmc.org/articles/PMC3216962?pdf=render |
| spellingShingle | Ran Levy Anat Biran Francoise Poirier Avraham Raz Yoel Kloog Galectin-3 mediates cross-talk between K-Ras and Let-7c tumor suppressor microRNA. PLoS ONE |
| title | Galectin-3 mediates cross-talk between K-Ras and Let-7c tumor suppressor microRNA. |
| title_full | Galectin-3 mediates cross-talk between K-Ras and Let-7c tumor suppressor microRNA. |
| title_fullStr | Galectin-3 mediates cross-talk between K-Ras and Let-7c tumor suppressor microRNA. |
| title_full_unstemmed | Galectin-3 mediates cross-talk between K-Ras and Let-7c tumor suppressor microRNA. |
| title_short | Galectin-3 mediates cross-talk between K-Ras and Let-7c tumor suppressor microRNA. |
| title_sort | galectin 3 mediates cross talk between k ras and let 7c tumor suppressor microrna |
| url | http://europepmc.org/articles/PMC3216962?pdf=render |
| work_keys_str_mv | AT ranlevy galectin3mediatescrosstalkbetweenkrasandlet7ctumorsuppressormicrorna AT anatbiran galectin3mediatescrosstalkbetweenkrasandlet7ctumorsuppressormicrorna AT francoisepoirier galectin3mediatescrosstalkbetweenkrasandlet7ctumorsuppressormicrorna AT avrahamraz galectin3mediatescrosstalkbetweenkrasandlet7ctumorsuppressormicrorna AT yoelkloog galectin3mediatescrosstalkbetweenkrasandlet7ctumorsuppressormicrorna |