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

2. 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

3. 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.

6. 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

8. 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).

9. 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

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

12. 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.

13. 3) Point mutation in a proto-oncogene :

17. ● 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

18. 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!)

20. 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

22. 2 “key” cancer-linked genes:
● ras proto-oncogene
● p53 tumor-suppressor gene

23. 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

24. 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!

26. 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:

28. 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…

29. 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

31. 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.

32. 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.

35. 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

38. 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!

39. Breast Cancer:
● in 5-10% of breast cancer cases, there is evidence of a strong inherited predisposition
● in , 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.

41. 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