ArticleMolecular and cellular biology2005
Pathway- and expression level-dependent effects of oncogenic N-Ras: p27(Kip1) mislocalization by the Ral-GEF pathway and Erk-mediated interference with Smad signaling.
Article in Molecular and cellular biology, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
What it found
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Who cites it
34 citing papers in PubMed, 54 citations in OpenAlex.
- UA-30 ameliorates motor deficits through RalA-mediated mitophagy in ALS mice.The Journal of clinical investigation · 2026Article
- Synthesis, molecular docking, and in-vitro studies of pyrimidine-2-thione derivatives as antineoplastic agents via potential RAS/PI3K/Akt/JNK inhibition in breast carcinoma cells.Scientific reports · 2022Article
- Competition between type I activin and BMP receptors for binding to ACVR2A regulates signaling to distinct Smad pathways.BMC biology · 2022Article
- A synthetic circuit for buffering gene dosage variation between individual mammalian cells.Nature communications · 2021Article
- TGFB1/INHBA Homodimer/Nodal-SMAD2/3 Signaling Network: A Pivotal Molecular Target in PDAC Treatment.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Review
- Ras Signaling in Breast Cancer.Advances in experimental medicine and biology · 2021Article
- Cholesterol depletion enhances TGF-β Smad signaling by increasing c-Jun expression through a PKR-dependent mechanism.Molecular biology of the cell · 2018Article
- Mitogen-activated protein kinase inhibitors reduce the nuclear accumulation of phosphorylated Smads by inhibiting Imp 7 or Imp 8 in HepG2 cells.Oncology letters · 2018Article
- The residue at position 5 of the N-terminal region of Src and Fyn modulates their myristoylation, palmitoylation, and membrane interactions.Molecular biology of the cell · 2016Article
- Association of cytoplasmic p27 expression with an unfavorable response to cisplatin-based chemotherapy and poor outcomes in non-small cell lung cancer.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
- Differential regulation of translation and endocytosis of alternatively spliced forms of the type II bone morphogenetic protein (BMP) receptor.Molecular biology of the cell · 2016Article
- Loss of p27Kip¹ promotes metaplasia in the pancreas via the regulation of Sox9 expression.Oncotarget · 2015Article
- Dab2 inhibits the cholesterol-dependent activation of JNK by TGF-β.Molecular biology of the cell · 2014Article
- Src-mediated caveolin-1 phosphorylation affects the targeting of active Src to specific membrane sites.Molecular biology of the cell · 2013Article
- Dual effects of Ral-activated pathways on p27 localization and TGF-β signaling.Molecular biology of the cell · 2013Article
- Flipping the switch from g1 to s phase with e3 ubiquitin ligases.Genes & cancer · 2012Article
- Expression of c-Jun, p73, Casp9, and N-ras in thymic epithelial tumors: relationship with the current WHO classification systems.Diagnostic pathology · 2012Article
- Coated pit-mediated endocytosis of the type I transforming growth factor-β (TGF-β) receptor depends on a di-leucine family signal and is not required for signaling.The Journal of biological chemistry · 2012Article
- p27kip1 protein levels reflect a nexus of oncogenic signaling during cell transformation.The Journal of biological chemistry · 2012Article
- Ran is a potential therapeutic target for cancer cells with molecular changes associated with activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways.Clinical cancer research : an official journal of the American Association for Cancer Research · 2012Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Overactivation of Ras pathways contributes to oncogenesis and metastasis of epithelial cells in several ways, including interference with cell cycle regulation via the CDK inhibitor p27(Kip1) (p27) and disruption of transforming growth factor beta (TGF-beta) anti-proliferative activity. Here, we show that at high expression levels, constitutively active N-Ras induces cytoplasmic mislocalization of murine and human p27 via the Ral-GEF pathway and disrupts TGF-beta-mediated Smad nuclear translocation by activation of the Mek/Erk pathway. While human p27 could also be mislocalized via the phosphatidylinositol 3-kinase/Akt pathway, only Ral-GEF activation was effective for murine p27, which lacks the Thr157 Akt phosphorylation site of human p27. This establishes a novel role for the Ral-GEF pathway in regulating p27 localization. Interference with either Smad translocation or p27 nuclear localization was sufficient to disrupt TGF-beta growth inhibition. Moreover, expression of activated N-Ras or specific effector loop mutants at lower levels using retroviral vectors induced p27 mislocalization but did not inhibit Smad2/3 translocation, indicating that the effects on p27 localization occur at lower levels of activated Ras. These findings have important implications for the contribution of activated Ras to oncogenesis and for the conversion of TGF-beta from an inhibitory to a metastatic factor in some epithelial tumors.
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Registered trials
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