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Chapt. 18 Cancer
Molecular Biology of Cancer
Student Learning Outcomes:
• Describe cancer – diseases in
which cells no longer respond
• Describe how cancers come from genomic
mutations (inherited or somatic)
• Explain how some gain of function mutations in
proto-oncogenes cause oncogenes
•
Growth factors, receptors, Ras, cyclins
• Explain how loss of function of tumorsuppressor genes leads to cancer
•
P53, Rb, regulators of Ras
Karyotype analysis can reveal translocation
Karyotype analysis reveals transloction of
chromosome 22 to 9 in CML
• chronic myelogenous leukemia has fusion protein
Bcr-Abl
Fig. 18.1
Cancers involve sequential mutations
Cancer involves sequential accumulation of
mutations in genes involved in normal cell
growth and differentiation:
• cancer cells do not
respond to normal
constraints
• cancer cells are immortal
• increasing abnormalities,
lack attachment
• Can inherit one bad gene
Fig. 18.1
Damage to DNA can lead to mutaitons
A. Chemical and physical agents
can damage DNA:
• Break DNA chains
• Cause translocations
• Modify bases
• DNA damage can be repaired;
mutations if not repaired
• Carcinogens are mutagens
• (see chapter 13)
Fig. 18.2 nitrosoamine causes
GC -> AT mutations
B. Gain-of-function mutations in Proto-ongogenes
Proto-oncogenes have normal roles for cell
growth, proliferation: Mutate to Oncogenes
• Mutate so function better.
in absence of normal
activating signals:
•
•
•
•
Overexpress
Hyperactive protein
Fusion protein
Controlled by other
promoter (inappropriate)
Fig. 18.3
Mutations in DNA repair enzymes can cause cancer:
Mutations in DNA repair enzymes can cause
cancer:
• DNA repair enzymes can correct damage
• They are tumor-suppressor genes
(need to mutate both)
• Breast cancer linked to Brca1, Brca2 mutations
• Xeroderma pigmentosum to excision repair
• HNPCC (hereditary nonpolyposis colorectal cancer)
linked to mutations in mismatch repair enzymes
Table 1 examples of oncogenes
Classes of oncogenes
Growth factor
platelet-derived growth factor
Growth factor receptor
platelet-derived gf receptor
Signal transduction
G-proteins
tyr kinase
Hormone receptors
retinoid receptor
Transcription factors
Cell-cycle regulators
cyclins
cyclin-dependent kinase
gene
mechanism
sis
overexpression
PDGFR
translocation
Ras
abl
point mutation
translocation
RARa
Myc
translocation
amplification
cyclin D
CDK4
amplification
point mutation
Oncogenes and signal transduction pathways
Growth factor signaling pathways provide sites
for proto-oncogene transforming mutations:
• Only need to mutate
one allele (one gene)
Dominant effect
• See Table 1
Fig. 18.4
Signal transduction proteins and phosphorylation cascade
Phosphorylation cascade from
activated Ras (Ras-GTP)
• Ras activates ser/thr kinase Raf
• Raf is a MAPKKK
(mitogen-activated protein Kinase
kinase kinase)
• Raf activates MEK
• (a MAPKK)
• MEK activates MAP kinase
• MAP kinase phosphorylates many
proteins
• Transcription factors can mutate to
oncogenes
• Mutations that keep proteins active
cause cell proliferation
Fig. 18.5
Oncogenes and the Cell cycle
Cyclins and cyclin-dependent kinases (CDK)
control passage through cell cycle:
• Different cyclins and CDKs control different points
• Cyclins transient; cdks persist
• Go is quiescent cell
• G1 -> S transition is critical
•
•
Commits to replication
Responds to hormones
• G2 -> M spindle check
Fig. 18.6
Cyclin-CDK
Cyclins are synthesized, function
to bind CDK, and degraded
CKIs are cyclin-dependent kinase
inhibitors
CDKs are also regulated:
• activated by PO4 (by CAK cyclinactivating kinases)
• inhibited by additional PO4
Oncogenes include:
• Overactive cyclins, mutant cdks
Fig. 18.7
Control of G1/S transition in cell cycle:
Control of G1/S is critical:
regulation of E2F by Rb, CDK, cyclin
CKI include p21, p16 (INK)
Fig. 18.8
IV. Tumor-suppressor genes
Tumor-suppressor genes encode proteins that
inhibit cell proliferation: mutate both copies
Table 18.2 class
protein
location
Adhesion protein
E-cadherin
cell surface
Signal transduction
NF-1
under membrane
p16 (INK4)
Rb
nucleus
nucleus
Cell cycle/ apoptosis
p53
nucleus
DNA repair
BRCA1
nucleus
Transcription factor
cell-cycle regulator
A. Some tumor suppressors regulate cell cycle directly
Retinoblastoma (Rb) protein binds E2F, prevents
transcription and G1/S until signal:(Fig. 18.8)
• Mutate both copies
• Cell loses control
• Hereditary cancer
tendency
Fig. 18.9
Phosphorylation controls transition G1 to S:
cycD-Cdk inactivates Rb ->E2F activates transcription
Genetics 15.12A
Phosphorylation controls transition G1 to S:
E2F activated transcription:
cyclins A, E and Cdk2 activate prereplication complexes
Genetics Fig 15.12 B
P53 is guardian of genome
P53 responds to DNA damage: stops cell cycle
to permit repair (or cell suicide – apoptosis)
• P53 mutated in 50% of tumors
• Induction of p21 stops cyclin-CDK
• Induction of GADD stops replicaiton, permits repair
Fig. 18.10
Some tumor suppressors affect receptors, signal transduction
1. Regulators of Ras are
tumor suppressors:
• GAP proteins (GTPase) bind
active Ras, stop signal
• NF-1 (neurofibromin) is GAP
for RAS in neuronal tissue
• Mutated NF-1 give
neurofibromatosis
Fig. 18.11
2. Tumor suppressors and proto-oncogenes
Tumor suppressors and
proto-oncogenes in path:
• Patched inhibits
Smoothened, coreceptor
• HH ligand binding releases
inhibition, activating signal
• S is proto-oncogene; mutation
can keep active
• P is tumor suppressor; mutations
ruining keep S active
Fig. 18.12
Tumor suppressor genes can affect cell adhesion
Tumor cells metastasize, lose cell adhesion:
• Normal adhesion from cadherins, link cytoskeleton
• Mutated cadherins promote cell migration
b-catenin also transcription factor;
•
•
Bound by inhibitor APC
APC is tumor suppressor
Fig. 18.13
Cancer involves sequential mutations
Cancer involves sequential
mutations that increase
aberrant cell activity:
2-hit model: mutations in at least
two different types of genes
(tumor suppressor, oncogene)
(also lack of apoptosis)
Fig. 18.18
Cancer is many different diseases
Cancer is many different diseases at the
molecular level:
• not all colon cancers have same defect
• defects in particular signaling pathways can cause
cancers in different tissues
Fig. 18.19
Viruses can also cause cancer
RNA retroviruses:
HTLV-1
adult T cell luekemia
HIV immunosuppression
non-Hodgkins lymphoma
Hepatitis C liver
DNA viruses:
HPV: cervical cancer
Epstein Barr (a herpesvirus) – interfere apoptosis
Review questions
2. The mechanism through which Ras becomes an
oncogenic protein is which of the following?
A. Ras remains bound to GAP
B. Ras can no longer bind cAMP
C. Ras has lost its GTPase activity
D. Ras can no longer bind GTP
E. Ras can no longer be phosphorylated by MAP
kinase