Transcript 8. Tumor Suppressor Genes

8.
้ งอก
ยีนย ับยงการเกิ
ั้
ดเนือ
(Tumor Suppressor Genes)
ว ัตถุประสงค์


สามารถบอกบทบาทของ tumor suppressor genes ใน cell
proliferation, cell death, DNA repair และ genetic
stability ได้
สามารถยกต ัวอย่าง และอธิบายกลไกในการย ับยงมะเร็
ั้
งของ
tumor suppressor genes ได้
้ หา
เนือ
8.1 Roles in cell proliferation and cell death
8.2 Roles in DNA repair and genetic stability
8. Tumor Suppressor Genes
 Tumor suppressor genes are genes whose loss or inactivation
can contribute to cancer development.
 Loss-of-function mutations of tumor suppressor genes can lead
to cancer.
8.1 Roles in cell proliferation and cell death
 Many tumor suppressor genes function to inhibit cell
proliferation or promote cell death.
 The loss of such functions would cause increased cell
proliferation or decreased cell death.
8.1.1 Cell fusion experiments provided the first evidence
for the existence of tumor suppressor genes
 In the late 1960s, hybrid
cell experiments provided
the earliest evidence that
normal cells contain genes
that can suppress tumor
growth and reestablish
normal controls on cell
proliferation.
 Reversion to malignant
behavior is associated with
the loss of certain
chromosomes.
---> loss of tumor
suppressor genes
Induced by
inactivated Sendai virus
8.1.2 Study of inherited chromosomal defects and loss of
heterozygosity have led to the identification of several
dozen tumor suppressor genes.
 Inherited chromosomal defect of RB: deleted segment in chromosome 13.
 Loss of Heterozygosity
Mitotic nondisjunction
Mitotic recombination
Gene conversion
8.1.3 The RB tumor suppressor gene produces a protein
that restrains passage through the restriction point.
 RB = the first tumor suppressor gene that was isolated and characterized.
 Rb protein restrains cell proliferation in the absence of growth factors.
 Cancers triggered by a loss of Rb function can arise in two fundamentally
different ways:
1) through mutations that delete or disrupt both copies of the RB gene.
2) through the action of viral oncoproteins that bind to and inactivate the Rb
protein (e.g. E7 oncoprotein from HPV)
 Since the discovery of the RB
gene in the mid-1980s, dozens
of additional tumor suppressor
genes have been identified.
8.1.4 The p53 tumor
suppressor gene
produces a protein
that prevents cells
with damaged DNA
from proliferating
 p53 = guardian of the
genome
 ATM kinase is produced by
the ATM tumor suppressor gene
: ATM = Ataxia Telangiectasia
Mutated
 Ataxia Telangiectasia
---> ~40% risk of developing
cancers (mostly lymphomas,
leukemias)
 Mdm2 = ubiquitin ligase
 Puma = p53 upregurated
modulator of apoptosis
 Ubiquitin plays a role in
targeting proteins for
degradation.
 p53 is the most commonly mutated gene in human cancers.
 Li-Fraumeni syndrome
inherit a mutant p53 gene.
---> high risk of developing
cancer
 However, most p53
mutations are not inherited.
 In some cases, mutation of
one copy of the p53 gene
may be sufficient to cause the
p53 protein to be inactivated.
---> “dominant negative
mutation”
 The E6 oncoprotein from
HPV binds to and targets p53
for destrution.
Comparison of Recessive and Dominant Negative p53 Mutations.
8.1.5 The APC tumor suppressor gene codes for a protein
that inhibits the Wnt signaling pathway.
 Associated with “familial adenomatus polyposis”.
---> ~100% risk of developing colon cancer ( age of 60)
---> < 1% of all colon cancer
 2/3 of all colon cancers involve APC mutations.
 APC gene codes for a protein involved in the Wnt pathway.
 -catenin is the central component of the Wnt pathway.
---> activates cell proliferation during embryonic development.
 Axin-APC-GSK3 destruction complex phosphorylates -catenin
---> -catenin is targeted by ubiquitin for degradation
 GSK3 = glycogen synthase kinase 3
8.1.6 The PTEN tumor suppressor gene codes for a
protein that inhibits the PI3K-Akt signaling pathway.
50% of prostate cancers and glioblastomas
----> PTEN mutations
PIP2 = Phosphatidylinositol-4,5-bisphosphate
PIP3 = Phosphatidylinositol-3,4,5-trisphosphate
Phosphatidylinositol 3-kinase
= PI 3-kinase or PI3K
8.1.7 Some tumor suppressor genes codes for
components of the TGF-Smad signaling pathway
 Transforming Growth Factor  (TGF )
may either stimulate or inhibit cell
proliferation, depending on the cell type
and context.
TGF  inhibits cell proliferation
through the TGF -Smad pathway.
Cdk inhibitors
 Loss-of-function mutations in the TGF  receptor are common in colon and
stomach cancers.
 Loss-of-function mutations in Smad proteins are observed in a variety of
cancers, including 50% of all pancreatic cancers and ~30% of colon cancers.
8.1.8 One genes produces two tumor suppressor
proteins: p16 and ARF
----> P16 and ARF exhibit no sequence similarity.
(INK4a)
ARF = Alternative Reading Frame
----> 15%-30% of all cancers originating in the breast, lung, pancreas, and bladder.
8.2 Roles in DNA repair and genetic stability
 Tumor suppressor genes involved in DNA maintenance and repair are
considered to be “caretakers” that preserve the integrity of the genome.
8.2.1 Genes involved in excision and mismatch repair
help prevent the accumulation of localized DNA errors
8.2.2 Proteins produced by the BRCA1 and BRCA2 genes assist in
the repair of double-strand DNA breaks
 Loss-of function of one of BRCA genes;
- risk of 40-80 % for breast cancer, 15-65 % for ovarian cancer.
- cells exhibit broken chromosomes, chromosomal translocations.
Repairing double-strand
DNA breaks by
Homologous
Recombination.
8.2.3 Mutation in genes that influence mitotic spindle behavior can
lead to chromosomal instabilities
Distributing Chromosomes During Mitosis
 The anaphase-promoting complex initiates chromosome movement by activating
separase, an enzyme that breaks down proteins called cohesins that hold the
duplicated chromosomes together.
 The “wait” signal that inhibits the anaphase-promoting complex are members of the
Mad and Bub families.
Genes coding for some of the Mad or Bub proteins behave as tumor suppressor gene.
 The loss of spindle checkpoint creates aneuploid cells.