M-Ras induces Ral and JNK activation to regulate MEK/ERK-independent gene expression in MCF-7 breast cancer cells

Ariel F. Castro, Tania Campos, Justin T. Babcock, Marisol E. Armijo, Alfonso Martínez-Conde, Roxana Pincheira, Lawrence Quilliam

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1253-1264
Number of pages12
JournalJournal of Cellular Biochemistry
Volume113
Issue number4
DOIs
StatePublished - Apr 2012

Fingerprint

Mitogen-Activated Protein Kinase Kinases
Gene expression
Chemical activation
Cells
Breast Neoplasms
Gene Expression
Phosphatidylinositol 3-Kinase
MCF-7 Cells
Carcinogenesis
ras Proteins
MAP Kinase Signaling System
Growth
Epidermal Growth Factor
Neoplasms
Estrogens
Tumors
Cell Line
Mutation

Keywords

  • Elk1
  • ESTROGEN
  • JNK
  • M-Ras
  • Ral
  • Rlf/Rgl2

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

M-Ras induces Ral and JNK activation to regulate MEK/ERK-independent gene expression in MCF-7 breast cancer cells. / Castro, Ariel F.; Campos, Tania; Babcock, Justin T.; Armijo, Marisol E.; Martínez-Conde, Alfonso; Pincheira, Roxana; Quilliam, Lawrence.

In: Journal of Cellular Biochemistry, Vol. 113, No. 4, 04.2012, p. 1253-1264.

Research output: Contribution to journalArticle

Castro, Ariel F. ; Campos, Tania ; Babcock, Justin T. ; Armijo, Marisol E. ; Martínez-Conde, Alfonso ; Pincheira, Roxana ; Quilliam, Lawrence. / M-Ras induces Ral and JNK activation to regulate MEK/ERK-independent gene expression in MCF-7 breast cancer cells. In: Journal of Cellular Biochemistry. 2012 ; Vol. 113, No. 4. pp. 1253-1264.
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