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Mdm2 requires Sprouty4 to regulate focal adhesion formation and metastasis independent of p53.
- Source :
-
Nature communications [Nat Commun] 2024 Aug 20; Vol. 15 (1), pp. 7132. Date of Electronic Publication: 2024 Aug 20. - Publication Year :
- 2024
-
Abstract
- Although the E3 ligase Mdm2 and its homologue and binding partner MdmX are the major regulators of the p53 tumor suppressor protein, it is now evident that Mdm2 and MdmX have multiple functions that do not involve p53. As one example, it is known that Mdm2 can regulate cell migration, although mechanistic insight into this function is still lacking. Here we show in cells lacking p53 expression that knockdown of Mdm2 or MdmX, as well as pharmacological inhibition of the Mdm2/MdmX complex, not only reduces cell migration and invasion, but also impairs cell spreading and focal adhesion formation. In addition, Mdm2 knockdown decreases metastasis in vivo. Interestingly, Mdm2 downregulates the expression of Sprouty4, which is required for the Mdm2 mediated effects on cell migration, focal adhesion formation and metastasis. Further, our findings indicate that Mdm2 dampening of Sprouty4 is a prerequisite for maintaining RhoA levels in the cancer cells that we have studied. Taken together we describe a molecular mechanism whereby the Mdm2/MdmX complex through Sprouty4 regulates cellular processes leading to increase metastatic capability independently of p53.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Animals
Cell Line, Tumor
Mice
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins genetics
Cell Cycle Proteins metabolism
Cell Cycle Proteins genetics
Membrane Proteins metabolism
Membrane Proteins genetics
Nuclear Proteins metabolism
Nuclear Proteins genetics
Gene Expression Regulation, Neoplastic
Proto-Oncogene Proteins c-mdm2 metabolism
Proto-Oncogene Proteins c-mdm2 genetics
Focal Adhesions metabolism
Focal Adhesions genetics
Tumor Suppressor Protein p53 metabolism
Tumor Suppressor Protein p53 genetics
Cell Movement genetics
Neoplasm Metastasis
rhoA GTP-Binding Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 39164253
- Full Text :
- https://doi.org/10.1038/s41467-024-51488-2