Up-regulation of SEPT9_v1 stabilizes c-Jun-N-terminal kinase and contributes to its pro-proliferative activity in mammary epithelial cells

Cell Signal. 2009 Apr;21(4):477-87. doi: 10.1016/j.cellsig.2008.11.007. Epub 2008 Nov 18.

Abstract

SEPT9_v1, the largest transcript of the septin gene family member, SEPT9, encodes a septin isoform implicated in the tumorigenic transformation of mammary epithelial cells. High levels of SEPT9_v1 expression also have been observed in both breast cancer cell lines, primary breast cancers as well as other solid tumor malignancies. We found a novel interaction between SEPT9_v1 and the c-Jun-N-terminal kinase (JNK), a mitogen-activated protein kinase important in cellular stress responses, cell proliferation, and cell survival. We found that up-regulation of SEPT9_v1 stabilizes JNK by delaying its degradation, thereby activating the JNK transcriptome. C-jun kinase assays in mammary epithelial cells expressing SEPT9_v1, compared to controls, exhibited increased JNK/c-Jun transcriptional activity. This increase was associated with increased levels of cyclin D1, a critical component of the proliferative response required for progression through G(1) of the cell cycle in many cell types. These findings demonstrate the first link between a septin protein and the JNK signaling pathway. Importantly, it suggests a novel functional role of SEPT9_v1 in driving cellular proliferation of mammary epithelial cells, a hallmark feature of oncogenesis that is directly relevant to breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / pathology
  • Cell Division / physiology
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cyclin D1 / physiology
  • Epithelial Cells / enzymology
  • Epithelial Cells / pathology
  • Female
  • GTP Phosphohydrolases / physiology*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • JNK Mitogen-Activated Protein Kinases / physiology*
  • Neoplasm Proteins / physiology*
  • Protein Isoforms / physiology
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / physiology
  • Septins
  • Sequence Deletion
  • Signal Transduction
  • Transduction, Genetic
  • Up-Regulation

Substances

  • CCND1 protein, human
  • Neoplasm Proteins
  • Protein Isoforms
  • Recombinant Fusion Proteins
  • Cyclin D1
  • JNK Mitogen-Activated Protein Kinases
  • GTP Phosphohydrolases
  • SEPTIN9 protein, human
  • Septins