The most harmful mutation
The main cause of the development of incurable cancer is named
Scientists led by chemist Neil Kelleher from Northwestern University have identified the most common cause of incurable cancer. It turned out that the growth of tumors can provoke specific mutations in RAS genes that affect the attachment of RAS proteins to cell membranes and their signaling role. This is reported in a press release on Medicalexpress (Study characterizes proteins resulting from RAS gene mutations, found in more than 20 percent of all human cancers).
The transformation of healthy cells into malignant cells is associated with a mutation in the RAS genes, which encode small G-proteins involved in signal transmission inside the cell. The RAS family includes genes encoding protein molecules such as HRAS, NRAS and two isoforms of KRAS (KRAS4a and KRAS4b). These proteins penetrate the cell membrane and bind to guanosine triphosphate (GTP), thereby changing their structure and switching to an activated state. Mutations that contribute to the development of cancer prevent the transition of RAS to an inactive state.
The structure of the KRAS4b isoform. Picture: Northwestern University
Oncogenic mutations often affect areas of proteins that should bind to GAP enzymes, creating new isoforms. GAP provoke hydrolysis (decomposition) of guanosine triphosphate to form guanosine diphosphate. Thus, an undesirable replacement of nucleotides either reduces the rate of hydrolysis of GTP, or completely cancels it. Constantly activated RAS causes excessive cell growth and proliferation.
RAS mutations are responsible for 30 percent of all human cancers, including 95 percent of pancreatic cancers and 45 percent of colorectal cancers. These malignant tumors are difficult to treat. This is partly due to the fact that different isoforms of proteins can create different signaling pathways that promote uncontrolled cell division, and each of them requires its own blocker drug.
Scientists isolated KRAS proteins from patients affected by colorectal cancer, as well as from tumor samples using specific antibodies. Further, each molecule was identified using a method called top-down proteomics, when the ratio of mass to ion charge of whole proteins is determined through mass spectrometry (with bottom-up proteomics, proteins are cleaved, analyzed, and then reassembled). The researchers were able to determine the content of the normal form of KRAS4b and its mutant versions in the cells of patients, as well as their structure.
It turned out that different mutations in KRAS4b have different effects on the posttranslational modification of the protein, when the protein molecule undergoes chemical modification after its synthesis on the ribosome. As a result, its ability to attach to the cell membrane and send signals that ensure normal cell division changes.
Article by Ioanna Ntai et al. Precise characterization of KRAS4b proteoforms in human colorectal cells and tumors reveals mutation/modification cross-talk published in the journal Proceedings of the National Academy of Sciences.
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