Sef downregulation by Ras causes MEK1/2 to become aberrantly nuclear localized leading to polyploidy and neoplastic transformation.

Stéphanie Duhamel; Josée Hébert; Louis Gaboury; Amélie Bouchard; Ronald Simon; Guido Sauter; Mark Basik; Sylvain Meloche

Sef downregulation by Ras causes MEK1/2 to become aberrantly nuclear localized leading to polyploidy and neoplastic transformation.

Standard

Sef downregulation by Ras causes MEK1/2 to become aberrantly nuclear localized leading to polyploidy and neoplastic transformation. / Duhamel, Stéphanie; Hébert, Josée; Gaboury, Louis; Bouchard, Amélie; Simon, Ronald ; Sauter, Guido; Basik, Mark; Meloche, Sylvain.

In: CANCER RES, Vol. 72, No. 3, 3, 2012, p. 626-635.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Duhamel, S, Hébert, J, Gaboury, L, Bouchard, A, Simon, R , Sauter, G, Basik, M & Meloche, S 2012, 'Sef downregulation by Ras causes MEK1/2 to become aberrantly nuclear localized leading to polyploidy and neoplastic transformation.', CANCER RES, vol. 72, no. 3, 3, pp. 626-635. <http://www.ncbi.nlm.nih.gov/pubmed/22298595?dopt=Citation>

APA

Duhamel, S., Hébert, J., Gaboury, L., Bouchard, A., Simon, R., Sauter, G., Basik, M., & Meloche, S. (2012). Sef downregulation by Ras causes MEK1/2 to become aberrantly nuclear localized leading to polyploidy and neoplastic transformation. CANCER RES, 72(3), 626-635. [3]. http://www.ncbi.nlm.nih.gov/pubmed/22298595?dopt=Citation

Vancouver

Duhamel S, Hébert J, Gaboury L, Bouchard A, Simon R , Sauter G et al. Sef downregulation by Ras causes MEK1/2 to become aberrantly nuclear localized leading to polyploidy and neoplastic transformation. CANCER RES. 2012;72(3):626-635. 3.

Bibtex

@article{02270525ce30481681ebd97c026820cc,

title = "Sef downregulation by Ras causes MEK1/2 to become aberrantly nuclear localized leading to polyploidy and neoplastic transformation.",

abstract = "Subcellular trafficking of key oncogenic signal pathway components is likely to be crucial for neoplastic transformation, but little is known about how such trafficking processes are spatially controlled. In this study, we show how Ras activation causes aberrant nuclear localization of phosphorylated mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) MEK1/2 to drive neoplastic transformation. Phosphorylated MEK1/2 was aberrantly located within the nucleus of primary colorectal tumors and human colon cancer cells, and oncogenic activation of Ras was sufficient to induce nuclear accumulation of phosphorylated MEK1/2 and ERK1/2 in intestinal epithelial cells. Enforced nuclear localization of MEK1 in epithelial cells or fibroblasts was sufficient for hyperactivation of ERK1/2, thereby driving cell proliferation, chromosomal polyploidy, and tumorigenesis. Notably, Ras-induced nuclear accumulation of activated MEK1/2 was reliant on downregulation of the spatial regulator Sef, the reexpression of which was sufficient to restore normal MEK1/2 localization and a reversal of Ras-induced proliferation and tumorigenesis. Taken together, our findings indicate that Ras-induced downregulation of Sef is an early oncogenic event that contributes to genetic instability and tumor progression by sustaining nuclear ERK1/2 signaling.",

keywords = "Animals, Humans, Female, Mice, Mice, Inbred BALB C, Rats, Immunoblotting, Cell Line, Tumor, Phosphorylation, Cell Line, Down-Regulation, Mice, Nude, Cell Nucleus/metabolism, NIH 3T3 Cells, Karyotyping, *Cell Transformation, Neoplastic, HCT116 Cells, Mitogen-Activated Protein Kinase 3/metabolism, Colorectal Neoplasms/genetics/metabolism/pathology, MAP Kinase Kinase 1/genetics/*metabolism, MAP Kinase Kinase 2/genetics/*metabolism, Mitogen-Activated Protein Kinase 1/metabolism, *Polyploidy, Receptors, Interleukin/genetics/*metabolism, ras Proteins/genetics/*metabolism, Animals, Humans, Female, Mice, Mice, Inbred BALB C, Rats, Immunoblotting, Cell Line, Tumor, Phosphorylation, Cell Line, Down-Regulation, Mice, Nude, Cell Nucleus/metabolism, NIH 3T3 Cells, Karyotyping, *Cell Transformation, Neoplastic, HCT116 Cells, Mitogen-Activated Protein Kinase 3/metabolism, Colorectal Neoplasms/genetics/metabolism/pathology, MAP Kinase Kinase 1/genetics/*metabolism, MAP Kinase Kinase 2/genetics/*metabolism, Mitogen-Activated Protein Kinase 1/metabolism, *Polyploidy, Receptors, Interleukin/genetics/*metabolism, ras Proteins/genetics/*metabolism",

author = "St{\'e}phanie Duhamel and Jos{\'e}e H{\'e}bert and Louis Gaboury and Am{\'e}lie Bouchard and Ronald Simon and Guido Sauter and Mark Basik and Sylvain Meloche",

year = "2012",

language = "English",

volume = "72",

pages = "626--635",

journal = "CANCER RES",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "3",

}

RIS

TY - JOUR

T1 - Sef downregulation by Ras causes MEK1/2 to become aberrantly nuclear localized leading to polyploidy and neoplastic transformation.

AU - Duhamel, Stéphanie

AU - Hébert, Josée

AU - Gaboury, Louis

AU - Bouchard, Amélie

AU - Simon, Ronald

AU - Sauter, Guido

AU - Basik, Mark

AU - Meloche, Sylvain

PY - 2012

Y1 - 2012

N2 - Subcellular trafficking of key oncogenic signal pathway components is likely to be crucial for neoplastic transformation, but little is known about how such trafficking processes are spatially controlled. In this study, we show how Ras activation causes aberrant nuclear localization of phosphorylated mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) MEK1/2 to drive neoplastic transformation. Phosphorylated MEK1/2 was aberrantly located within the nucleus of primary colorectal tumors and human colon cancer cells, and oncogenic activation of Ras was sufficient to induce nuclear accumulation of phosphorylated MEK1/2 and ERK1/2 in intestinal epithelial cells. Enforced nuclear localization of MEK1 in epithelial cells or fibroblasts was sufficient for hyperactivation of ERK1/2, thereby driving cell proliferation, chromosomal polyploidy, and tumorigenesis. Notably, Ras-induced nuclear accumulation of activated MEK1/2 was reliant on downregulation of the spatial regulator Sef, the reexpression of which was sufficient to restore normal MEK1/2 localization and a reversal of Ras-induced proliferation and tumorigenesis. Taken together, our findings indicate that Ras-induced downregulation of Sef is an early oncogenic event that contributes to genetic instability and tumor progression by sustaining nuclear ERK1/2 signaling.

AB - Subcellular trafficking of key oncogenic signal pathway components is likely to be crucial for neoplastic transformation, but little is known about how such trafficking processes are spatially controlled. In this study, we show how Ras activation causes aberrant nuclear localization of phosphorylated mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) MEK1/2 to drive neoplastic transformation. Phosphorylated MEK1/2 was aberrantly located within the nucleus of primary colorectal tumors and human colon cancer cells, and oncogenic activation of Ras was sufficient to induce nuclear accumulation of phosphorylated MEK1/2 and ERK1/2 in intestinal epithelial cells. Enforced nuclear localization of MEK1 in epithelial cells or fibroblasts was sufficient for hyperactivation of ERK1/2, thereby driving cell proliferation, chromosomal polyploidy, and tumorigenesis. Notably, Ras-induced nuclear accumulation of activated MEK1/2 was reliant on downregulation of the spatial regulator Sef, the reexpression of which was sufficient to restore normal MEK1/2 localization and a reversal of Ras-induced proliferation and tumorigenesis. Taken together, our findings indicate that Ras-induced downregulation of Sef is an early oncogenic event that contributes to genetic instability and tumor progression by sustaining nuclear ERK1/2 signaling.

KW - Animals

KW - Humans

KW - Female

KW - Mice

KW - Mice, Inbred BALB C

KW - Rats

KW - Immunoblotting

KW - Cell Line, Tumor

KW - Phosphorylation

KW - Cell Line

KW - Down-Regulation

KW - Mice, Nude

KW - Cell Nucleus/metabolism

KW - NIH 3T3 Cells

KW - Karyotyping

KW - Cell Transformation, Neoplastic

KW - HCT116 Cells

KW - Mitogen-Activated Protein Kinase 3/metabolism

KW - Colorectal Neoplasms/genetics/metabolism/pathology

KW - MAP Kinase Kinase 1/genetics/metabolism

KW - MAP Kinase Kinase 2/genetics/metabolism

KW - Mitogen-Activated Protein Kinase 1/metabolism

KW - Polyploidy

KW - Receptors, Interleukin/genetics/metabolism

KW - ras Proteins/genetics/metabolism