Transcript NOTES: CH 18 part 2 - Molecular Basis of Cancer (powerpoint)

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 protooncogene’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 protooncogene :
● increases the # of copies of the gene in a
cell through repeated gene duplication
3) Point mutation in a protooncogene (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 protooncogene :
● 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: TUMORSUPPRESSOR 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