Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors

Abstract

The 41-kDa and 43-kDa mitogen-activated protein (MAP) kinases play a pivotal role in the mitogenic signal transduction pathway and are essential components of the MAP kinase cascade, which includes MAP kinase kinase (MEK) and Raf-1. As aberrant activation of signal transducing molecules such as Ras and Raf-1 has been linked with cancer, we examined whether constitutive activation of the 41-/43-kDa MAP kinases is associated with the neoplastic phenotype of 138 tumor cell lines and 102 primary tumors derived from various human organs. Constitutive activation of the MAP kinases was observed in 50 tumor cell lines (36.2%) in a rather tissue-speci®c manner: cell lines derived from pancreas, colon, lung, ovary and kidney showed especially high frequencies with a high degree of MAP kinase activation, while those derived from brain, esophagus, stomach, liver and of hematopoietic origin showed low frequencies with a limited degree of MAP kinase activation. We also detected constitutive activation of the 41-/43-kDa MAP kinases in a relatively large number of primary human tumors derived from kidney, colon and lung tissues but not from liver tissue. Many tumor cells, in which point mutations of ras genes were detected, showed constitutive activation of MAP kinases, however, there were also many exceptions to this observation. In contrast, the activation of the 41-/43-kDa MAP kinases was accompanied by the activation of Raf-1 in the majority of tumor cells and was completely associated with the activation of MEK and p90 rsk in all the tumor cells examined. These results suggest that the constitutive activation of 41-/43-kDa MAP kinases in tumor cells is not due to the disorder of MAP kinases themselves, but is due to the disorder of Raf-1, Ras, or some other signaling molecules upstream of Ras.

Doxorubicin and vinorelbine act independently via p53 expression and p38 activation respectively in breast cancer cell lines

“…The two drugs principally act via different mechanisms: doxorubicin intercalates among DNA base pairs resulting in conformational changes in DNA structure and changes in the activity of topoisomerases, whereas vinorelbine is known to disrupt microtubules in the mitotic spindle formation, inducing metaphase arrest during mitosis (Perry, 1996). Constitutive MAPK and p38 activity was confirmed in the MDA-MB-468 and MCF-7 breast cancer cell lines (Sivaraman et al, 1997;Hoshino et al, 1999). However, when vinorelbine was administered, increased p38 activity was shown in both cell lines.…”

Targeting inhibition of K-ras enhances Ad.mda-7-induced growth suppression and apoptosis in mutant K-ras colorectal cancer cells

“…In their constitutively active, deregulated GTP-bound form (e.g., by point mutation), p21 Ras stimulates a signaling cascade promoting cancer cell growth (Barbacid, 1987). Evidence of increased signaling through the Ras-ERK pathway is suggested by the observation that activated phosphorylated ERK1/2 is expressed in a high proportion of tumor cell lines and primary tumor-derived cell cultures from the colon (Hoshino et al, 1999). In the present study, we employed two approaches to inhibit K-ras expression and downstream signaling, a single-chain neutralizing Figure 5 Effect of infection of colorectal carcinoma cells with Ad.vec, Ad.mda-7, Ad.K-ras scAb and Ad.K-ras AS, alone and in combination with Ad.mda-7, or Ad.m7.KAS viruses on BCL-family protein expression.…”

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

“…This choice was not arbitrary, as this pathway is one of the major downstream signalling pathways from EGFR. Activated ERK1/2 control many processes that are central to malignant progression, including cell growth, apoptosis and migration (Pages et al, 1993;Campbell et al, 1995;Hoshino et al, 1999;Schramek, 2002). Disrupting regulation of the MAPK pathway can predispose cells to undergo tumorigenic transformation, as illustrated by the position of the ras oncogene upstream of ERK (Zhang et al, 1993).…”