MDM2 promotes cell motility and invasiveness by regulating E-cadherin degradation

Jer Yen Yang, Cong S. Zong, Weiya Xia, Yongkun Wei, Mohamed Ali-Seyed, Zheng Li, Kristine Broglio, Donald A. Berry, Mien Chie Hung

Research output: Contribution to journalArticle

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Abstract

Gene amplification and protein overexpression of MDM2, which is often found in certain types of cancers, indicate that MDM2 plays an important role in tumorigenesis. Interestingly, several clinical reports have demonstrated that amplification of the MDM2 gene correlates with the metastatic stage. Using an antibody array assay, we identified E-cadherin as an MDM2-binding protein and confirmed that E-cadherin is a substrate for the MDM2 E3 ubiquitin ligase. We demonstrate that MDM2 interacts in vivo with E-cadherin, resulting in its ubiquitination and degradation. This regulation appears to be clinically relevant, as we found a significant correlation between high MDM2 and low E-cadherin protein levels in resected tumor specimens recovered from breast cancer patients with lymph node metastases. Ectopic expression of MDM2 in breast cancer cells was found to disrupt cell-cell contacts and enhance cell motility and invasive potential. We found that E-cadherin and MDM2 colocalized on the plasma membrane and in the early endosome, where ubiquitin moieties were attached to E-cadherin. Blocking endocytosis with dominant-negative mutants of dynamin abolished the association of MDM2 with E-cadherin, prevented E-cadherin degradation, and attenuated cell motility as observed by fluorescence microscopy. Thus, we provide evidence to support a novel role for MDM2 in regulating cell adhesions by a mechanism that involves degrading and down-regulating the expression of E-cadherin via an endosome pathway. This novel MDM2-regulated pathway is likely to play a biologically relevant role in cancer metastasis.

Original languageEnglish
Pages (from-to)7269-7282
Number of pages14
JournalMolecular and Cellular Biology
Volume26
Issue number19
DOIs
Publication statusPublished - Oct 2006
Externally publishedYes

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Cadherins
Cell Movement
Gene Amplification
Endosomes
Breast Neoplasms
Neoplasm Metastasis
Dynamins
Neoplasms
Ubiquitin-Protein Ligases
Ubiquitination
Ubiquitin
Endocytosis
Fluorescence Microscopy
Cell Adhesion
Carrier Proteins
Carcinogenesis
Proteins
Lymph Nodes
Cell Membrane
Antibodies

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Yang, J. Y., Zong, C. S., Xia, W., Wei, Y., Ali-Seyed, M., Li, Z., ... Hung, M. C. (2006). MDM2 promotes cell motility and invasiveness by regulating E-cadherin degradation. Molecular and Cellular Biology, 26(19), 7269-7282. https://doi.org/10.1128/MCB.00172-06

MDM2 promotes cell motility and invasiveness by regulating E-cadherin degradation. / Yang, Jer Yen; Zong, Cong S.; Xia, Weiya; Wei, Yongkun; Ali-Seyed, Mohamed; Li, Zheng; Broglio, Kristine; Berry, Donald A.; Hung, Mien Chie.

In: Molecular and Cellular Biology, Vol. 26, No. 19, 10.2006, p. 7269-7282.

Research output: Contribution to journalArticle

Yang, JY, Zong, CS, Xia, W, Wei, Y, Ali-Seyed, M, Li, Z, Broglio, K, Berry, DA & Hung, MC 2006, 'MDM2 promotes cell motility and invasiveness by regulating E-cadherin degradation', Molecular and Cellular Biology, vol. 26, no. 19, pp. 7269-7282. https://doi.org/10.1128/MCB.00172-06
Yang, Jer Yen ; Zong, Cong S. ; Xia, Weiya ; Wei, Yongkun ; Ali-Seyed, Mohamed ; Li, Zheng ; Broglio, Kristine ; Berry, Donald A. ; Hung, Mien Chie. / MDM2 promotes cell motility and invasiveness by regulating E-cadherin degradation. In: Molecular and Cellular Biology. 2006 ; Vol. 26, No. 19. pp. 7269-7282.
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