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Siva1 suppresses epithelial-mesenchymal transition and metastasis of tumor cells by inhibiting stathmin and stabilizing microtubules.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2011 Aug 02; Vol. 108 (31), pp. 12851-6. Date of Electronic Publication: 2011 Jul 18. - Publication Year :
- 2011
-
Abstract
- Epithelial-mesenchymal transition (EMT) enables epithelial cells to acquire motility and invasiveness that are characteristic of mesenchymal cells. It plays an important role in development and tumor cell metastasis. However, the mechanisms of EMT and their dysfunction in cancer cells are still not well understood. Here we report that Siva1 interacts with stathmin, a microtubule destabilizer. Siva1 inhibits stathmin's activity directly as well as indirectly through Ca(2+)/calmodulin-dependent protein kinase II-mediated phosphorylation of stathmin at Ser16. Via the inhibition of stathmin, Siva1 enhances the formation of microtubules and impedes focal adhesion assembly, cell migration, and EMT. Low levels of Siva1 and Ser16-phosphorylated stathmin correlate with high metastatic states of human breast cancer cells. In mouse models, knockdown of Siva1 promotes cancer dissemination, whereas overexpression of Siva1 inhibits it. These results suggest that microtubule dynamics are critical for EMT. Furthermore, they reveal an important role for Siva1 in suppressing cell migration and EMT and indicate that down-regulation of Siva1 may contribute to tumor cell metastasis.
- Subjects :
- Animals
Apoptosis Regulatory Proteins genetics
Blotting, Western
Breast Neoplasms genetics
Breast Neoplasms metabolism
Breast Neoplasms pathology
Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism
Cell Line, Tumor
Cell Movement
Female
HEK293 Cells
Humans
Immunoprecipitation
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Metastasis
Neoplasms genetics
Neoplasms pathology
Neoplasms, Experimental genetics
Neoplasms, Experimental metabolism
Neoplasms, Experimental pathology
Phosphorylation
Protein Binding
RNA Interference
Serine genetics
Serine metabolism
Stathmin genetics
Apoptosis Regulatory Proteins metabolism
Epithelial-Mesenchymal Transition
Microtubules metabolism
Neoplasms metabolism
Stathmin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 108
- Issue :
- 31
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 21768358
- Full Text :
- https://doi.org/10.1073/pnas.1017372108