Inhibition of nuclear accumulation of phosphorylated ERK by tropomyosin-1-mediated cytoskeletal reorganization

Shantaram Bharadwaj, Girish Vasanth, Laura Masuelli, Ruchi Thanawala, G. L. Prasad

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

AIM: Most neoplastic cells express diminished levels of tropomyosin (TM) family of actin-binding proteins, which leads to the formation of poorly organized cytoskeleton. The aberrant cytoskeleton is hypothesized to contribute to the neoplastic phenotype through deregulation of intracellular signaling. The aim of the study is to evaluate whether reorganization of cytoskeleton modulates signaling pathways. Methods: We have utilized ras-transformed NIH3T3 (DT) cells and those transduced with TM1 (DT/TM1) as a model system. DT cells are highly malignant whereas the DT/TM1 cells contain reorganized cytoskeleton and exhibit revertant phenotype. Activation status of ras oncogene in DT and DT/TM1 cells was measured by GTP loading. Activation status and subcellular localization of extracellular signal regulated kinase (ERK) was measured in total, cytoplasmic and nuclear compartments by immunoblotting and confocal microscopy. Results: Transduction of TM1 does not alter the activation status of oncogenic ras. Both parental DT and DT/TM1 cells exhibit similar levels of activated ERK in total cellular lysates, whereas DT/TM1 cells contain significantly less phosphorylated ERK pERK) in the nuclear fraction. Disruption of cytosekeletal integrity results in increased nuclear content of pERK, suggesting that tropomyosin-1-induced microfilaments are critical for curtailing the nuclear accumulation of activated ERK, and may contribute to the anti-oncogenic effects of TM1. Conclusion: Our data suggest that spatiotemporal regulation of ERK by cytoskeleton is an important mechanism. Furthermore, aberrant microfilaments, present in neoplastic cells, fail to restrict nuclear localization of ERK, and hence contribute to deregulated ERK signaling.

Original languageEnglish (US)
Pages (from-to)139-144
Number of pages6
JournalJournal of Cancer Molecules
Volume4
Issue number5
StatePublished - 2008
Externally publishedYes

Keywords

  • Compartmentalization
  • Cytoskeleton
  • ERK
  • Ras
  • Subcellular
  • Tropomyosin-1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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