Cell Growth, Cancer and Oncogenes
How Oncogenes Cause Cancer
Cancer Genes in the Human Genome
How Oncogenes Cause Cancer
The change of an oncogene from normal to cancerous function can be caused by a simple point mutation in the sequence of a gene. For example, a change in the ras oncogene, located on human chromosome 11, from guanine to cytosine is frequently associated with bladder cancer. This simple change results in glycine at amino acid #12 being substituted with a valine. This dramatically changes the function of the G-protein encoded by the ras gene. Normally, the protein cycles from an inactive to active state by change the bound GDP to GTP. The mutation does not allow the release of GTP, and the protein is continuously active. Because the signal delivered by the ras oncoprotein is continuously delivered, the cell continues to grow and divide. This unabated growth leads to the bladder cancer.
Deletions of the ligand binding domain of the EGFR oncogene, located on human chromosome 7, results in continuous signal transduction by the epidermal growth factor receptor it encodes. The deletion protein can form a dimer even in the absence of the epidermal growth factor. Dimerization leads to continuous tyrosine kinase activity and uncontrolled activation of the signal transduction pathway associated with this gene.
The following table summarizes the types of molecular changes that can be associated with the activation of an oncogene.
| Molecular Change | Effect On Oncogene |
|---|---|
| Translocation | Philadelphia chromosome contains a bcr1/abl fusion that activates the abl protein kinase activity; Burkitt lymphoma result from the placement of the c-myc next to an enhancer in B lymphocytes |
| Point Mutations | See ras discussion above |
| Deletions | See v-erbB discussion above |
| Insertional activation | A retrovirus without an oncogene may insert near a protooncogene and activate the protooncogene by increasing its expression 30-100 fold. This activation is not immediate, but can take several months. The LTRs of retroviruses contain powerful promoters and enhancer sequences that presumably are responsible for the increased expression. The insertion can occur on either side of the protooncogene or in its intron. This type of activation has been associated with c-myc and c-myb. |
| Amplification | Amplification of the protooncogene has also been associated with the onset of cancer. This has been best studied in cell culture. |
Copyright © 1997. Phillip McClean