M-Ras induces Ral and JNK activation to regulate MEK/ERK-independent gene expression in MCF-7 breast cancer cells
| Autor: | Lawrence A. Quilliam, Tania Campos, Marisol E. Armijo, Alfonso Martínez-Conde, Roxana Pincheira, Justin T. Babcock, Ariel F. Castro |
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| Rok vydání: | 2012 |
| Předmět: |
MAPK/ERK pathway
Cell type MAP Kinase Kinase 4 Cell Biology medicine.disease_cause Biochemistry Gene Expression Regulation Enzymologic Article ELK1 Cell Line Tumor medicine Humans Immunoprecipitation Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Monomeric GTP-Binding Proteins Cell Biology Cell biology Enzyme Activation medicine.anatomical_structure MCF-7 Cancer research Female ral GTP-Binding Proteins Mitogen-Activated Protein Kinases Carcinogenesis Signal Transduction |
| Zdroj: | Journal of Cellular Biochemistry. 113:1253-1264 |
| ISSN: | 0730-2312 |
| Popis: | Constitutive activation of M-Ras has previously been reported to cause morphologic and growth transformation of murine cells, suggesting that M-Ras plays a role in tumorigenesis. Cell transformation by M-Ras correlated with weak activation of the Raf/MEK/ERK pathway, although contributions from other downstream effectors were suggested. Recent studies indicate that signaling events distinct from the Raf/MEK/ERK cascade are critical for human tumorigenesis. However, it is unknown what signaling events M-Ras triggers in human cells. Using constitutively active M-Ras (Q71L) containing additional mutations within its effector-binding loop, we found that M-Ras induces MEK/ERK-dependent and -independent Elk1 activation as well as phosphatidylinositol 3 kinase (PI3K)/Akt and JNK/cJun activation in human MCF-7 breast cancer cells. Among several human cell lines examined, M-Ras-induced MEK/ERK-independent Elk1 activation was only detected in MCF-7 cells, and correlated with Rlf/M-Ras interaction and Ral/JNK activation. Supporting a role for M-Ras signaling in breast cancer, EGF activated M-Ras and promoted its interaction with endogenous Rlf. In addition, constitutive activation of M-Ras induced estrogen-independent growth of MCF-7 cells that was dependent on PI3K/Akt, MEK/ERK, and JNK activation. Thus, our studies demonstrate that M-Ras signaling activity differs between human cells, highlighting the importance of defining Ras protein signaling within each cell type, especially when designing treatments for Ras-induced cancer. These findings also demonstrate that M-Ras activity may be important for progression of EGFR-dependent tumors. |
| Databáze: | OpenAIRE |
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