Up-regulation of SEPT9_v1 stabilizes c-Jun-N-terminal kinase and contributes to its pro-proliferative activity in mammary epithelial cells.
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.
Gonzalez
Maria E
ME
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States.
Makarova
Olga
O
Peterson
Esther A
EA
Privette
Lisa M
LM
Petty
Elizabeth M
EM
D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000502:physiology; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D005260:Female; D020558:GTP Phosphohydrolases / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000502:physiology; D058112:Septins; D017384:Sequence Deletion; D015398:Signal Transduction; D014161:Transduction, Genetic; D015854:Up-Regulation
C530104:CCND1 protein, human; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D019938:Cyclin D1; D048031:JNK Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; C474315:SEPTIN9 protein, human; D058112:Septins