Oncogenes

uncle genes are genes that code for proteins that normally direct cell growth they start out as proto-oncogenes and then something happens to convert that proto-oncogene into a full-blown uncle gene an essence some sort of tumor inducing agent or it could also be totally spontaneous now proto-oncogenes code for proteins that help to regulate cell growth and differentiation which makes sense since the essence of a tumor whether it is a cancerous or benign one is unregulated cell growth in fact the words uncle gene and oncology which is the study of cancer share the same root word uncles which is Greek for mass or bulk now the products of these genes are often involved in signal transduction and the execution of mitogenic signals and you should call that a mitogen is a chemical substance that encourages a cell to start cell division basically something that triggers mitosis so how does a proto-oncogene make that switch into an oncogene well there are three main mechanisms deletion or point mutation gene amplification or increased mRNA stability and chromosomal rearrangement so let's start the first one deletion or point nutation and coding sequence of the DNA in the gene itself or within a regulatory region such as a promoter region can lead to either a protein that is produced in the same normal amounts but is hyperactive for some reason or maybe there is some sort of loss of regulation and the normal protein is just over expressed gene amplification or an increase in mRNA stability that prolongs the existence of the mRNA and thus the its activity in the cell can lead to a normal protein that is overexpressed and then finally chromosomal rearrangement involves translocation of a gene to a nearby regulatory sequence that then causes the it's normal protein the gene product to be over expressed or you could possibly have fusion to and actively transcribed gene which over expresses the fusion protein or leads to a hyperactive fusion protein and so really you can start to see a theme here emerging where the key idea is that you have either a normal protein that is just over expressed basically too much of the normal protein or you can have normal expression but the protein itself is just a hyperactive one now there are tons of examples of oncogenes including the SAR cocking wrasse Micke receptor tyrosine kinase and also cytoplasmic tyrosine kinases so let's talk about each one of those here Sark was the first confirmed oncogenes which was discovered in 1970 and was termed Sark for sarcoma which is a tumor of mesenchymal cells or connective tissue cells it was actually an oncogene discovered in a chicken retrovirus and so stark codes for a non receptor protein tyrosine kinase so it phosphorylates specific tyrosine residues and other proteins another example of an oncogene is the Rass encode gene which codes for a small gtp ace which hydrolyzes GTP into gdp and phosphate this protein is activated by growth factor signaling and functions like a binary switch sort of an on-off switch in growth signaling pathways examples of downstream effectors of rass includes the protein map k which is a type of kinase that in turn regulates genes that mediate cell proliferation you can see examples of rats on Kijiji mutations and thyroid tumors certain leukemias and cancers of the pancreas and colon the Mik uncle gene codes for a transcription factor that induces cell proliferation and there's a very common translocation involving Mik between chromosomes 8 where the Mik onca gene is found and 14 which leads to a certain type of lymphoma called Burkitt's lymphoma the RTK oncogene stands for receptor tyrosine kinase which is responsible for adding phosphate groups to other proteins to turn them on or off these are similar to the SARC gene which is a non receptor tyrosine kinase the difference being the location of the protein either at the cell surfaces receptor or not as a receptor so say you have a cell surface receptor that sees a signal from outside of the cell well then that signal gets propagated or transmitted into the cell via these receptor tyrosine kinases that add phosphate groups to the target protein specifically on tyrosine residues and they can cause cancer by turning a receptor constitutively or permanently on in the absence of signals from outside the cell some well known examples of receptor tyrosine kinases are vascular endothelial growth factor or veg F epidermal growth factor or EGFR and platelet derived growth factor PDGF and finally we have the cytoplasmic tyrosine kinases which mediate responses to the activation of receptors of cell proliferation migration differentiation and survival a well-known example is the BCR Abel gene in chronic myelogenous leukemia or CML also known as the Philadelphia chromosome it is a fusion of parts of DNA from chromosome 22 and chromosome 9 so basically a part of chromosome 22 which contains the BCR gene fuses with a fragment from chromosome 9 which contains the ABL gene when these two chromosome fragments fuse the genes also fuse creating this new gene the bcr-abl gene the fuse gene codes for a protein that displays high protein tyrosine kinase activity which is actually due to the ABL half of the protein and the unregulated expression of this protein activates other proteins that are involved in cell cycle cell division which causes a cell to grow and divide uncontrollably basically becoming cancerous so as a result the Philadelphia chromosome is associated with chronic myelogenous leukemia a certain type of leukemia as I mentioned before as well as other forms of leukemias which are cancers of white blood cells