a the chromosomal instability pathway which influences proto oncogenes and tumor suppressor genes and it is characterized by alterations of chromosomal number and framework, and b the microsatellite instabil ity pathway, accountable also for Lynch syndrome CRCs, which capabilities size variations of repeated nucleo tides mainly in non coding sequences, due to defects inside the mismatch repair program, Along with CIN and MSI pathways, a third pathway, the epigenetic instability, which can be imagined to get largely driven by hypermethylation induced silencing of tumor suppres sor like genes, has become implicated inside the progression of colorectal carcinogenesis, According to this notion, modern literature suggests that CRC in general develops by two independent pathways that involve sequences of genetic and epigenetic alterations associated with pathological and clinical characteristics.
the adenoma buy inhibitor pathway in 70 80% and also the newly recognized, the serrated pathway from the remaining twenty 30%, The somatic molecular characteristics which characterize the newly introduced serrated pathway to CRC include activating mutations in B raf and widespread hypermethylation of gene promoters with or without MSI, The kinases of mitogen activated protein kinase superfamily participate in signaling cascades con served via evolution, which transduce extracellular signals into intracellular responses. MAP kinases are important parts of pathways controlling embryogen esis, cell differentiation, proliferation and death.
The Ras Raf mitogen extracellular signal regulated kinase one two extracellular signal regulated kinase 1 two cascade is activated by mitogenic factors, dif ferentiation stimuli and cytokines, Delanzomib The Raf family of protein kinases, which is one class of Ras effectors, phosphorylates the dual distinct MAP kinases MEK1 and MEK2, which in turn phosphorylate and activate the effector MAP kinases ERK1 and ERK2, ERKs are multifunctional serine threonine kinases that target a huge array of substrates localized in all cellular compart ments, including protein kinases, signaling effectors, receptors, cytoskeletal and nuclear proteins and tran scription elements, that can influence cell fate, Importantly, MAP kinases are capable of affecting gene expression by way of intermediary kinases by phosphory lating proteins within the cytoplasm, but also translocate towards the nucleus, a essential step for the fulfilment of lots of cellular functions of ERK, for instance gene transcription, cell proliferation and differentiation, Via phos phorylation of those many substrates, constitutively activated ERKs are able to influence a lot of the hall marks of carcinogenesis, as defined by Hanahan and Weinberg, Constitutive activation of this pathway has been observed in quite a few human malignancies and cell lines which include breast, colon, thyroid carcinomas and melanomas and gives a potent promitogenic force resulting in uncontrolled proliferation and differentia tion, The current study investigates the presence of muta tions in K ras and B raf genes in colorectal carcinoma, in correlation with MAP kinase ERK expression as well as the expression of mismatch restore proteins hMLH1 and hMSH2, trying to elucidate the involvement of these MAP kinases from the growth of colorectal cancer, at the same time as their correlations with conventional clini copathological parameters.