NOTES: CH 18 part 2 - The Molecular Biology of Cancer

Certain genes normally regulate cell growth & division – the cell cycle. ● mutations that alter these genes in somatic cells can lead to cancer ● mutations may be spontaneous or the result of exposure to a MUTAGEN / CARCINOGEN

GENES & CANCER: ● ONCOGENES = cancer-causing genes, first found in certain retroviruses ● subsequently, close counterparts have been found in the genomes of humans & other animals ● PROTO-ONCOGENES = normal cellular genes that code for proteins that stimulate normal cell growth & division.

How Might a Proto-Oncogene Become an Oncogene? ● In general, an oncogene arises from a genetic change that leads to an INCREASE in either:  the amount of the proto-oncogene’s protein product;  the intrinsic activity of each protein molecule

The genetic changes that convert proto-oncogenes to oncogenes fall into 3 categories: 1) Movement of DNA within the genome; 2) Amplification of a proto-oncogene; 3) Point mutation in an oncogene (or one of its control elements).

1) Movement of DNA within the genome: ● chromosomes may break and then rejoin incorrectly, translocating fragments from 1 chromosome to another ● a proto-oncogene may now lie adjacent to a more active promoter ● or, an active promoter may move by transposition to the region just upstream of the proto-oncogene, increasing its expression

2) Amplification of a proto-oncogene : ● increases the # of copies of the gene in a cell through repeated gene duplication

3) Point mutation in a proto-oncogene (or a control element): ● changes the gene’s protein product to one that is more active or more resistant to degradation than the normal protein… ● or could be a point mutation in the promoter of a gene, causing an increase in its expression; …all of these changes can lead to abnormal stimulation of the cell cycle and put the cell on the path to malignancy.

3) Point mutation in a proto-oncogene :

● the changes considered thus far affect growth-stimulating proteins… ● however, changes in genes whose normal products INHIBIT cell division also contribute to cancer… ● such genes are called: TUMOR-SUPPRESSOR GENES

Tumor-Suppressor Genes: ● the proteins encoded by these genes normally help to prevent uncontrolled cell growth. ● any mutation that decreases the normal activity of a tumor-suppressor protein may contribute to the onset of cancer (stimulates growth through the absence of suppression!)

Tumor-Suppressor Genes – What Do They Do? They may encode a protein that… ● repairs damaged DNA (prevents cell from accumulating cancer-causing mutations) ● controls the adhesion of cells to each other or to an extracellular matrix (proper cell anchorage is crucial in normal tissues) ● are components of cell-signaling pathways that inhibit the cell cycle

2 “key” cancer-linked genes: ● ras proto-oncogene ● p53 tumor-suppressor gene

ras proto-oncogene: ● mutations in the ras gene are found in about 30% of human cancers ● the product is the Ras protein ● the Ras protein is a G protein that relays a growth signal from a growth factor receptor on the plasma membrane to a cascade of protein kinases

ras proto-oncogene: ● the response: synthesis of a protein that stimulates the cell cycle ● many ras oncogenes have a point mutation that leads to a hyperactive version of the Ras protein that signals on its own… ● the outcome: excessive cell division!

p53 tumor-suppressor gene: ● mutations in the p53 gene are found in about 50% of human cancers ● the product of the p53 gene is a protein that is transcription factor that promotes synthesis of growth-inhibiting proteins… ● so, a mutation knocking out the p53 gene can lead to excessive cell growth & cancer ● the p53 protein acts in several ways to prevent a cell from passing on mutations or damaged DNA:

p53 gene: ● the p53 gene has been called the “guardian angel of the genome”… ● once the p53 gene is activated – for example, by DNA damage – the p53 protein functions as an activator for several other genes…

p53 protein: (1) activates a gene (p21) whose product halts the cell cycle, allowing time for the cell to repair any damaged DNA; (2) can turn on genes directly involved in DNA repair; (3) Activates expression of a group of miRNAs, which in turn inhibit the cell cycle; (4) when DNA damage is irreparable, p53 activates “suicide” genes, whose protein products cause cell death by APOPTOSIS

p53 protein: ● thus, p53 acts in several ways to prevent a cell from passing on mutations due to DNA damage; ● if mutations do accumulate and the cell survives through many divisions (as is more likely if the p53 tumor-suppressor gene is defective or missing), cancer may ensue.

Multiple mutations underlie the development of cancer. ● more than 1 somatic mutation is generally needed to produce a full-fledged cancer cell; ● this may help explain why the incidence of cancer increases greatly with age… ● if cancer is the result of an accumulation of mutations, & if mutations occur throughout life, then the longer we live, the more likely we are to develop cancer.

Colorectal Cancer: ● about 135,000 new cases per year in the U.S. ● develops gradually – first sign usually a POLYP (small, benign growth in colon lining) ● the tumor grows and eventually may become MALIGNANT ● a malignant tumor will typically have cells with multiple oncogenes activated and multiple tumor-suppressor genes inactivated

Remember TELOMERES?  ● in many malignant tumors, the gene for TELOMERASE is activated… ● this enzyme prevents the erosion of the ends of chromosomes (the telomeres), thus removing a natural limit on the # of times the cells can divide…the tumor cells just keep on growing!

Breast Cancer: ● in 5-10% of breast cancer cases, there is evidence of a strong inherited predisposition ● in 1994-1995, researcher identified 2 genes involved these breast cancers: BRCA1 and BRCA2 ● both are considered tumor-suppressor genes (their wild-type alleles protect against breast cancer) ● what the normal products of BRCA1 and BRCA2 actually do is still unknown…it seems as though they are both involved in the cell’s DNA damage repair pathway.

Viruses & Cancer: ● viruses seem to play a role in about 15% of human cancer cases worldwide EXAMPLES: ● retroviruses  some forms of leukemia ● hepatitis viruses  some liver cancers ● HPV  cancer of the cervix