Section S Tumor viruses and oncogenes

S1 ONCOGENES FOUND IN TUMOR VIRUSES Cancer Cancer results from mutations that disrupt the controls regulating normal cell growth. Oncogenes Oncogenes are genes whose overactivity causes cells to become cancerous. Oncogenic retroviruses Oncogenic retroviruses were the source of the first oncogenes to be isolated. Isolation of oncogenes The isolation of oncogenes was aided by the development of an assay which tests the ability of DNA to transform the growth pattern of NIH-3T3 mouse fibroblasts.

S1 ONCOGENES FOUND IN TUMOR VIRUSES Fig. 1. Testing for the presence of an oncogene in DNA by revealing its ability to cause a change in the growth pattern of NIH-3T3 cells.

S1 ONCOGENES FOUND IN TUMOR VIRUSES Fig. 2. The mechanism by which MMTV causes cancer in mouse mammary cells. (a) The mouse int-2 gene before integration of the MMTV provirus; (b) integration of the provirus results in overexpression of int-2.

S2 CATEGORIES OF ONCOGENS Oncogenes and growth factors Many oncogenes code for proteins that take part in various steps in the mechanism by which cells respond to growth factors. Nuclear oncogenes Other oncogenes code for nuclear DNA-binding proteins that act as transcription factors regulating the expression of other genes involved in cell division. Co–operation between oncogenes When normal rat fibroblasts taken straight from the animal are transfected with oncogenes, it is found that both a growth factor-related and a nuclear oncogene are required to convert the cells to full malignancy.

S2 CATEGORIES OF ONCOGENS Fig. 1. The fms oncogene codes for a growth factor receptor that is mutated so that it is constitutively active.

S3 TUMOR SUPPRESSOR GENES Overview Tumor suppressor genes cause to become cancerous when they are mutated to become inactive. Evidence for tumor suppressor genes Evidence includes the behavior of hybrid cells formed by fusing normal and cancerous cells, patterns of inheritance of certain familial cancers and ‘loss of heterozygosity’ for chromosome markers in tumor cells. RB1 gene The RB1 gene was the first tumor suppressor gene to be isolated. p53 gene p53 is the tumor suppressor gene that is mutated in the largest number of different types of tumor.

S3 TUMOR SUPPRESSOR GENES Fig. 1. Loss of heterozygosity is the process whereby a cell loses a portion of a chromosome that contains the only active allele of a tumor suppressor gene.

S3 TUMOR SUPPRESSOR GENES Fig. 2. Retinoblastoma results from the inactivation of both copies of the RB1 gene on chromosome 13. This can occur by mutation of both normal copies of the gene (sporadic retinoblastoma) or by inheritance of one inactive copy followed by an acquired mutation in the remaining functional copy (familial retinoblastoma).

S3 TUMOR SUPPRESSOR GENES Fig. 3. The dominant–negative effect of a mutated p53 gene results from the ability of the protein to dimerize with and inactivate the normal protein.

S4 APOPTOSIS Apoptosis Apoptosis is an important pathway that results in cell death in multi-cellular organisms. Removal of damaged or dangerous cells Apoptosis has an important role in removing damaged or dangerous cells, for example in prevention of autoimmunity or in response to DNA damage. Cellular changes during apoptosis In apoptosis, the chromatin in the cell nucleus condenses and the DNA becomes fragmented. Apoptosis in C. elegans The ced-3 and ced-4 genes are required for cell death, which can be suppressed by the product of the ced-9 gene, the absence of which results in excessive apoptosis. Apoptosis in mammals The mammals homolog of C.elegans ced-9 is bcl-2, which acts to suppress apoptosis. Apoptosis in disease and cancer Defects in apoptosis are important in disease and cancer. Some proto-oncogenes such as bcl-2 prevent apoptosis, reflecting the role of apoptosis-suppression in tumor formation.

S4 APOPTOSIS Fig. 1. Apoptosis. a) A characteristic DNA ladder from cells undergoing apoptosis. b) A microscopic image of T-cells showing apoptotic bodies (apoptotic cell marked with an arrow, original picture from Dr D. Spiller). c) A schematic diagram of the stages of apoptosis.