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Article
Cytoplasmic Metadherin (MTDH) provides survival advantage under conditions of stress by acting as RNA-binding protein
The Journal of biological chemistry
  • Xiangbing Meng, University of Iowa
  • Danlin Zhu, University of Iowa
  • Shujie Yang, University of Iowa
  • Xinjun Wang, University of Iowa
  • Zhi Xiong, University of Iowa
  • Yuping Zhang, University of Iowa
  • Pavla Brachova, University of Iowa
  • Kimberly K. Leslie, University of Iowa
Document Type
Article
Peer Reviewed
1
Publication Date
2-10-2012
NLM Title Abbreviation
J Biol Chem
PubMed ID
22199357
DOI of Published Version
10.1074/jbc.C111.291518
Abstract

Overexpression of metadherin (MTDH) has been documented in many solid tumors and is implicated in metastasis and chemoresistance. MTDH has been detected at the plasma membrane as well as in the cytoplasm and nucleus, and the function of MTDH in these locales remains under investigation. In the nucleus, MTDH acts as a transcription co-factor to induce expression of chemoresistance-associated genes. However, MTDH is predominantly cytoplasmic in prostate tumors, and this localization correlates with poor prognosis. Herein, we used endometrial cancer cells as a model system to define a new role for MTDH in the cytoplasm. First, MTDH was primarily localized to the cytoplasm in endometrial cancer cells, and the N-terminal region of MTDH was required to maintain cytoplasmic localization. Next, we identified novel binding partners for cytoplasmic MTDH, including RNA-binding proteins and components of the RNA-induced silencing complex. Nucleic acids were required for the association of MTDH with these cytoplasmic proteins. Furthermore, MTDH interacted with and regulated protein expression of multiple mRNAs, such as PDCD10 and KDM6A. Depletion of cytoplasmic MTDH was associated with increased stress granule formation, reduced survival in response to chemotherapy and the tyrosine kinase inhibitor BIBF1120, Rad51 nuclear accumulation, and cell cycle arrest at G(2)/M. Finally, in vivo tumor formation was abrogated with knockdown of cytoplasmic MTDH. Taken together, our data identify a novel function for cytoplasmic MTDH as an RNA-binding protein. Our findings implicate cytoplasmic MTDH in cell survival and broad drug resistance via association with RNA and RNA-binding proteins.

Keywords
  • Amino Acid Sequence,
  • Animals,
  • Apoptosis Regulatory Proteins,
  • Cell Adhesion Molecules/genetics/metabolism,
  • Cell Line,
  • Tumor,
  • Cell Nucleus/genetics/metabolism,
  • Cell Survival/physiology,
  • Cytoplasm/genetics/metabolism,
  • Drug Resistance,
  • Neoplasm/physiology,
  • Female,
  • Histone Demethylases/genetics/metabolism,
  • Humans,
  • Male,
  • Membrane Proteins,
  • Mice,
  • Mice,
  • Nude,
  • Nuclear Proteins/genetics/metabolism,
  • Protein Biosynthesis/physiology,
  • Protein Structure,
  • Tertiary,
  • Proto-Oncogene Proteins,
  • RNA,
  • Messenger/genetics/metabolism,
  • RNA-Binding Proteins/genetics/metabolism,
  • Sequence Deletion,
  • Stress,
  • Physiological/physiology
Published Article/Book Citation
The Journal of biological chemistry (2012) 287:7, pp. 4485-4491.
Citation Information
Xiangbing Meng, Danlin Zhu, Shujie Yang, Xinjun Wang, et al.. "Cytoplasmic Metadherin (MTDH) provides survival advantage under conditions of stress by acting as RNA-binding protein" The Journal of biological chemistry Vol. 287 Iss. 7 (2012) p. 4485 - 4491 ISSN: 1083-351X
Available at: http://works.bepress.com/xiangbing_meng/24/