Scientists led by chemist Neil Calleja (Neil Kelleher) from northwestern University has identified the most frequent cause of incurable cancer.
It turned out that the growth of tumors can trigger specific mutations in RAS genes affecting the accession of RAS proteins to cell membranes and their signaling role. About it reported in a press release on MedicalXpress.
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The transformation of healthy cells to malignant is associated with mutations in the RAS genes that encode small G-proteins involved in signal transmission inside cells. The RAS family includes genes encoding such protein molecules as HRAS, NRAS and KRAS isoforms (KRAS4a and KRAS4b). These proteins penetrate the cell membrane and bind with guanosine triphosphate (GTP), thereby changing its structure and switching in an activated state. Mutations contributing to cancer, inhibiting RAS in after installation without the condition.
Oncogenic mutations often affect the areas of proteins, which must bind with enzymes in the GAP, creating new isoforms. GAP provoke the hydrolysis (disintegration) of guanosine triphosphate with the formation of guanosine diphosphate. Thus, the undesirable replacement of nucleotides or reduces the rate of hydrolysis of GTP, or completely negate it. Constantly activated RAS leads to excessive growth and proliferation of cells.
RAS mutations are responsible for 30 percent of all cancers in humans, including 95% of pancreatic cancers and 45 percent of colorectal cancer. These malignant tumors are difficult to treat. This is partly due to the fact that different isoforms of proteins can create a variety of signaling pathways that promote uncontrolled cell division, and for each of them requires its own drug-blocker.
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Scientists have identified KRAS-proteins in patients affected with colorectal cancer, as well as from samples of tumors using specific antibodies. Further, each molecule identified using a method called proteomics top-down (top-down proteomics) when using mass spectrometry determines the mass-to-charge ions of entire proteins (in proteomics “bottom-up” proteins are broken down, analyzed and then re-collected). The researchers were able to determine the content of the normal form KRAS4b and its mutant versions in cells from patients as well as their structure.
It turned out that different mutations in KRAS4b different effects on the post-translational modification of the protein when the protein molecule is chemically modified after its synthesis on the ribosome. Changes as a result of its ability to adhere to the membrane of cells and send signals that ensure normal cell division.