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