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

• Published in: Cellular signalling Vol. 21; no. 4; pp. 477 - 487
• Main Authors: Gonzalez, Maria E., Makarova, Olga, Peterson, Esther A., Privette, Lisa M., Petty, Elizabeth M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-04-2009
• Subjects: Breast Neoplasms - enzymology; Breast Neoplasms - pathology; Cell cycle regulation; Cell Division - physiology; Cell Line, Transformed; Cell Line, Tumor; Cell proliferation; Cyclin D1 - physiology; Cyclins; Epithelial Cells - enzymology; Epithelial Cells - pathology; Female; Gene Expression Regulation, Neoplastic; GTP Phosphohydrolases - physiology; Humans; JNK; JNK Mitogen-Activated Protein Kinases - physiology; Mammary epithelial cells; Neoplasm Proteins - physiology; Oncogenesis; Protein Isoforms - physiology; Protein Structure, Tertiary; Recombinant Fusion Proteins - physiology; Septins; Sequence Deletion; Signal Transduction; Transduction, Genetic; Up-Regulation; Cell proliferation; Mammary epithelial cells; JNK; Septins; Oncogenesis; Cell cycle regulation; Cyclins
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2008.11.007

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.