NOTES: CH 18 part 2 – The Molecular Biology of Cancer (18.5)
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 =
, 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
.
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
;
 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:
● chromosomes may break and then rejoin incorrectly, translocating fragments from 1 chromosome to another
● a proto-oncogene may now lie
● or, an active promoter may move by transposition to the region just upstream of the proto-oncogene,
2) Amplification of a proto-oncogene :
● increases the
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
or
than the normal protein;
● or could be a point mutation in the promoter of a gene, causing an
…all of these changes can lead to
;
and put the cell on the
path to malignancy.
● 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
.
● any mutation that decreases the normal activity of a tumor-suppressor protein may contribute to the onset of
cancer (
!)
Tumor-Suppressor Genes – What Do They Do?
They may encode a protein that…
●
(prevents cell from accumulating cancer-causing mutations)
●
or to an extracellular matrix (proper cell anchorage is
crucial in normal tissues)
● are components of cell-signaling pathways that
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
from a growth factor receptor on the
plasma membrane to a cascade of
● the response: synthesis of a protein that
● many ras oncogenes have a point mutation that leads to a
…
● the outcome:
!
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 transcription factor that
…
● so, a mutation knocking out the p53 gene can lead to
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:
● the p53 protein acts in several ways to prevent a cell from passing on mutations or damaged DNA:
(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
(4) when DNA damage is irreparable, p53
;
“
”
, whose protein
products cause cell death by APOPTOSIS
● thus, p53 acts in several ways to
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 tumorsuppressor gene is defective or missing),
.
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
…
● 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
and multiple
Remember TELOMERES? 
● in many malignant tumors, the gene for TELOMERASE is activated…
● this enzyme
(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
(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 
● hepatitis viruses 
● HPV 