RGD Reference Report - Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors. - Rat Genome Database

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Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors.

Authors: Voisin, Laure  Julien, Catherine  Duhamel, Stéphanie  Gopalbhai, Kailesh  Claveau, Isabelle  Saba-El-Leil, Marc K  Rodrigue-Gervais, Ian Gaël  Gaboury, Louis  Lamarre, Daniel  Basik, Mark  Meloche, Sylvain 
Citation: Voisin L, etal., BMC Cancer. 2008 Nov 17;8:337. doi: 10.1186/1471-2407-8-337.
RGD ID: 13464351
Pubmed: PMID:19014680   (View Abstract at PubMed)
PMCID: PMC2596176   (View Article at PubMed Central)
DOI: DOI:10.1186/1471-2407-8-337   (Journal Full-text)


BACKGROUND: The Ras-dependent ERK1/2 MAP kinase signaling pathway plays a central role in cell proliferation control and is frequently activated in human colorectal cancer. Small-molecule inhibitors of MEK1/MEK2 are therefore viewed as attractive drug candidates for the targeted therapy of this malignancy. However, the exact contribution of MEK1 and MEK2 to the pathogenesis of colorectal cancer remains to be established.
METHODS: Wild type and constitutively active forms of MEK1 and MEK2 were ectopically expressed by retroviral gene transfer in the normal intestinal epithelial cell line IEC-6. We studied the impact of MEK1 and MEK2 activation on cellular morphology, cell proliferation, survival, migration, invasiveness, and tumorigenesis in mice. RNA interference was used to test the requirement for MEK1 and MEK2 function in maintaining the proliferation of human colorectal cancer cells.
RESULTS: We found that expression of activated MEK1 or MEK2 is sufficient to morphologically transform intestinal epithelial cells, dysregulate cell proliferation and induce the formation of high-grade adenocarcinomas after orthotopic transplantation in mice. A large proportion of these intestinal tumors metastasize to the liver and lung. Mechanistically, activation of MEK1 or MEK2 up-regulates the expression of matrix metalloproteinases, promotes invasiveness and protects cells from undergoing anoikis. Importantly, we show that silencing of MEK2 expression completely suppresses the proliferation of human colon carcinoma cell lines, whereas inactivation of MEK1 has a much weaker effect.
CONCLUSION: MEK1 and MEK2 isoforms have similar transforming properties and are able to induce the formation of metastatic intestinal tumors in mice. Our results suggest that MEK2 plays a more important role than MEK1 in sustaining the proliferation of human colorectal cancer cells.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Objects Annotated

Genes (Rattus norvegicus)
Map2k1  (mitogen activated protein kinase kinase 1)
Map2k2  (mitogen activated protein kinase kinase 2)

Genes (Mus musculus)
Map2k1  (mitogen-activated protein kinase kinase 1)
Map2k2  (mitogen-activated protein kinase kinase 2)

Genes (Homo sapiens)
MAP2K1  (mitogen-activated protein kinase kinase 1)
MAP2K2  (mitogen-activated protein kinase kinase 2)


Additional Information