Activating mutations inside the three RAS genes, most fre quently in KRAS, are already uncovered in 30% of human neoplasias and therefore are frequently an early event in tumor progres sion. Particularly, KRAS mutations are detected in somewhere around 35% of all sporadic colorectal adenomas and carcinomas. Genetic and biochemical research have firmly established the central role of Ras GTPases in regulating cell proliferation, growth and survival. More than ten distinct courses of Ras effectors are recognized to date, several of which are associated with oncogenic signaling pathways. The best characterized of the Ras effector pathways could be the activation with the Raf relatives Ser Thr kinases, leading to sequential phosphor ylation and activation of MEK1 MEK2 as well as mitogen activated protein kinases ERK1 ERK2. The significance of Raf in oncogenic signaling has become vali dated by the discovery of activating BRAF mutations in a wide range of human tumors.
which includes 14% of colorectal cancers. Raf relays its oncogenic signals largely through the MAP kinase kinases MEK1 and MEK2. Early studies have shown that expression of activated alleles of MEK1 is ample to deregulate the proliferation and trigger the morphological transformation of immortalized fibroblast and epithelial cell lines. In vivo, orthotopic transplan tation of mammary epithelial cells expressing selleck activated MEK1 into syngeneic mice rapidly generated invasive ade nocarcinomas. Transgenic expression of active MEK1 in mouse skin induced hyperplasia, hyperkeratosis and perturbed differentiation in the epidermis. Con versely, treatment with MEK1 2 inhibitors was proven to inhibit the proliferation of a variety of carcinoma and leuke mic cell lines. Notably, administration of an orally available inhibitor of MEK1 two elicited marked anti tumor efficacy in mouse xenograft versions of colon cancer and metastatic melanoma.
In parallel, several scientific studies using clinical specimens have documented the up regulation and or activation of MEK1 MEK2 plus the MAP kinases ERK1 ERK2 in reliable tumors and leukemias. Collectively, these findings have supplied strong rationale for the growth of little molecule inhibitors of MEK1 2 for chemotherapeu tic intervention in cancer. MEK1 and MEK2 show 85% amino acid identity overall and therefore are expressed over here ubiquitously in cell lines and tissues. While it truly is usually assumed the two isoforms are functionally equivalent, a number of lines of proof, even so, indicate they are regulated differentially and may perhaps exert non redundant functions. Scientific studies making use of RNA interference have advised that both MEK1 and MEK2 are essential for in vitro cell proliferation, and they contribute to distinct cell cycle regulatory occasions. Even so, the individual roles of MEK1 and MEK2 in tumorigenesis stay to become explored.