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

Abstract

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.

Interleukin-1β production in human monocytes/macrophages is differentially regulated by MEK1 upon sterile and infectious inflammatory conditions

“…Although MEK1 and MEK2 activities are rarely distinguished in the literature, growing evidence indicates that MEK1 and MEK2 may be differentially regulated and exert non-redundant functions [42][43][44][45][46][47][48][49][50][51]. That MEK1 and MEK2 play different roles in the regulation of several cellular processes implies that either substrate other than ERK1/2 might be differentially phosphorylated by MEK1 and MEK2, or MEK1/2 functions that do not directly require kinase activity, or both [29,52].…”

Activation of the ERK1/2 pathway by the CaMEK gene via adeno-associated virus serotype 9 in cardiomyocytes

“…Recently, transfection of constitutive activation of the mitogen-activated protein kinase kinase 1 (CaMEK) into cells has been reported to promote ERK1/2 expression; activated ERKs then translocate into the nucleus, where they activate nuclear transcription factors such as Elk-1, c-fos, and c-jun, thereby regulating cell proliferation and differentiation (Treisman, 1996;Manning et al, 2002). Such proliferative effects of CaMEK in confluent cells of an intestinal epithelial line (IEC-6) have been reported, and the silencing of MEK expression significantly reduces the extent of ERK1/2 phosphorylation, inhibiting cell proliferation (Voisin et al, 2008). MEK1 transgenic mice have also been shown to be resistant to I/R injury and have significantly reduced myocardial infarct size (Lips et al, 2004).…”

Deregulated ERK1/2 MAP kinase signaling promotes aneuploidy by a Fbxw7β-Aurora A pathway

“…IEC-6 cell populations co-expressing MEK1DD, H-Ras V12 or Aurora A constructs with H2B-GFP were obtained by simultaneous infection with pBabe-puro-MEK1DD or pBabe-puro-H-Ras V12 or pBabe-puro-Aurora A and pCLNR-Neo-H2B-GFP, followed by selection with puromycin and G418. Infection with shRNA-expressing lentiviruses was carried out as described 47 and cells were selected with puromycin.…”