Transcript 7. Oncogenes

7.
อองโคยีน (Oncogenes)
ว ัตถุประสงค์


สามารถอธิบายกลไกการเปลีย
่ น proto-oncogenes ไปเป็น
oncogenes ได้
สามารถยกต ัวอย่าง oncogenes และอธิบายกลไกในการก่อ
มะเร็งของ oncogenes ได้
้ หา
เนือ
7.1 How cellular oncogenes arise
7.2 Proteins produced by Oncogenes
7. ONCOGENES
Oncogenes are genes whose presence can contribute to
uncontrolled cell proliferation and cancer.
7.1 How cellular oncogenes arise
Oncogenes can arise inside cells in two fundamentally
different ways.
1. A mechanism involves the participation of viruses
that introduce oncogenes into the cells they infect.
2. A series of mechanisms that convert normal cellular
genes into oncogenes, often as a result of exposure to
carcinogenic agents.
7.1.1 Cellular oncogenes arise from Protooncogenes
Proto-oncogenes are normal cellular genes
- can be converted into oncogenes
- contribute to the regulation of cell proliferation and
survival
The mutations of proto-oncogenes can cause cancer.
- gain-of-function mutations can induce tumor
formation
7.1.2 Cellular oncogenes were initially detected
in gene transferred experiment
Transfection with tumor cell DNA
The DNA of bladder cancer cells contains genetic
information, not present in normal DNA, that is capable of
causing cancer (early 1980s, Robert Weinberg and Geoffrey Cooper) .
 RAS oncogene was the first
human oncogene to be
identified.
- DNA sequence is related to vras oncogene
- ras ---> ”rat sarcoma”
 RAS proto-oncogene
produces a protein involved in a
normal pathway for stimulating
cell proliferation.
 Oncogenes cannot always be
detected using DNA transfection
techniques.
Inducing cancer by DNA transfection.
Kleinsmith LJ. Principles of cancer biology.
Pearson International Edition. Benjamin
Cummings, San Francisco. 2006. p.37.
 The mechanisms by which cellular oncogenes arise can be grouped
into 5 basic categories:
1. point mutation
2. gene amplification
3. chromosomal translocation
4. DNA rearrangement
5. insertional mutagenesis
7.1.3 Mechanism 1: Point mutations can convert protooncogenes into oncogenes
Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco. 2006. p.160.
 RAS oncogenes produced by point mutation have been detected in
many types of cancers.
----> cancers of bladder, lung, colon, pancreas, and thyroid.
 Carcinogens such as asbestos, vinyl chloride, and
dimethylbenzanthracene each trigger mutations at different locations
within the RAS gene.
7.1.4 Mechanism 2: Gene Amplification can convert
proto-oncogenes into oncogenes
 DNA located in a specific chromosomal region is replicated
numerous time in succession.
----> creating dozens, hundreds, or thousands of copies of the same
stretch of DNA.
 Chromosome regions containing amplified genes often exhibit a
distinctive, abnormal appearance that can be recognized when
chromosomes are examined by light microscopy.
----> homogeneously staining regions (HSRs) and double minutes
(DMs).
Appearance of chromosome regions containing Amplified DNA
Kleinsmith LJ. Principles of cancer biology. Pearson International Edition.
Benjamin Cummings, San Francisco. 2006. p.161.
 Gene amplification typically yields oncogenes that produce normal
proteins but in excessive quantities.
 Members of MYC gene family, MYC, MYCL, and MYCN, are among
the most commonly encountered oncogenes to arise by gene
amplification in human cancers.
MYC ----> detected in cancers of the breast, ovary, uterine cervix,
lung, and esophagus.
MYCN ----> detected in neuroblastoma
 Tumor with higher copy numbers of the amplified oncogenes tend
to exhibit poorer survival rates.
----> more likely to invade and metastasize
Kleinsmith LJ. Principles
of cancer biology.
Pearson International
Edition. Benjamin
Cummings, San Francisco.
2006. p.161.
7.1.5 Mechanism 3: Chromosomal translocation can
convert proto-oncogenes into oncogenes
 A piece of one chromosome is broken off and moved to another
chromosome.
 Chromosomal translocations contribute to cancer development by;
1) fusing two gene together to form an oncogene coding for a
fusion protein
BCR= Breakpoint cluster region
ABL= Abelson murine leukemia
viral oncogene homolog
Tyrosine Kinase activity 
---> Philadelphia chromosome is associated with 90% of all cases
of chronic myelogenous leukemia (CML).
2) activating the expression of a proto-oncogene by placing it
near a highly active gene
Highly active
antibody genes
---> Burkitt’s lymphoma; the entire MYC proto-oncogene is moved
from chromosome 8 to 14.
7.1.6 Mechanism 4: Local DNA rearrangements can
convert proto-oncogenes into oncogenes
 DNA rearrangements disrupt the expression or structure of a protooncogene located in that region.
 Types of DNA rearrangements;
1) Deletion
2) Insertion
3) Transposition
4) Inversion
 DNA rearrangements are frequently detected in human tumor cells,
especially in certain types of cancer.
----> thyroid cancers (nearly 50%)
 The TRK oncogene is a
fusion gene created by a
chromosomal inversion
that brings together
segments of two genes,
TMP3 and NTRK1, residing
on the same chromosome.
 The fusion protein
forms a permanent dimer
and its tyrosine kinase is
permanently activated.
 The fusion protein acts as
a permanently activated
receptor that continually
stimulates cell proliferation,
regardless of whether its
growth factor is present.
7.1.7 Mechanism 5: Insertional mutagenesis can convert
proto-oncogenes into oncogenes
 Retrovirus randomly inserts its genes near a proto-oncogene.
 The retroviral LTRs may stimulate transcription of the protooncogene and trigger overproduction of a normal cellular protein that
can contribute to cancer development.
7.1.8 Summary: Cellular oncogenes arise from protooncogenes by mechanisms that alter gene structure or
expression.
7.2 Proteins produced by Oncogenes
 More than 100 oncogenes have been identified to date.
 Most of the proteins produced by oncogenes are components of
signaling pathways that promote cell proliferation and survival.
 Oncogenes disrupt normal signaling mechanisms and foster the
excessive proliferation and inappropriate survival of cancer cells by
producing abnormal versions or excessive quantities of proteins
involved in these pathways.
 Proteins produced by oncogenes fall into a variety of categories,
including;
1) growth factors
2) receptors
3) enzymes that catalyze protein phosphorylation
4) proteins that bind to and regulate the activity of DNA or
other proteins
Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco. 2006.
p.166.
Kleinsmith LJ. Principles of cancer biology. Pearson International Edition. Benjamin Cummings, San Francisco. 2006.
p.166.
7.2.1 Oncogenes typically code for components of
signaling pathways that activate cell proliferation
 Growth factor triggers proliferation by activating signaling
pathways involving dozens of molecules within the targeted cell.
Ras-MAPK
Pathway
(ERK)
Grb2=growth-factor-receptor-binding protein 2
SOS = ‘son of sevenless’
KSR = kinase suppressor of Ras
PP2A = protein phosphatase 2A
MEK = MAPK/ERK kinase
ERK = extracellular-signal-regulated kinase
MAPK = Mitogen-Activated Protein Kinase
PAK = p21rac/cdc42-activated kinase
7.2.2 Some oncogenes produce growth factors
 Growth factors stimulate the cell proliferation that is required
during events such as embryonic development, tissue regeneration,
and wound repair.
 No growth factor ----> progression through the cell cycle is halted
during G1 (at the restriction point) and cell proliferation ceases.
 PDGF (platelet-derived growth factor)
----> produced by blood platelets
----> stimulates the proliferation of connective tissue cells
 EGF (epidermal growth factor)
----> widely distributed in normal tissues
----> acts on a variety of cell types, mainly (but not exclusively) of
epithelial origin
 Oncogenes
v-sis ----> PDGF , simian sarcoma virus, sarcomas (monkeys)
COL1A1-PDGFB ----> PDGF, chromosomal translocation,
fibrosarcoma
7.2.3 Some oncogenes produce receptor proteins
 membrane receptor ----> acts as a protein kinase
Examples:
----> v-erb-b
----> RET
----> TRK
Examples:----> ERBB2 (member of EGF
receptor family)
Mutant receptor
Amplified receptor
7.2.4 Some Oncogenes produce plasma membrane G proteins
 Ras protein----> a member of G proteins
 Human RAS ----> HRAS, KRAS, NRAS
 RAS mutations are detected in roughly 30% of all human cancers
----> the most commonly encountered type of human oncogene
 KRAS ----> the most frequently mutated in human cancers
----> 30% of lung cancers, 50% of colon cancers, 90% of
pancreatic cancers
 NRAS ----> 25% of acute leukemias
 HRAS ----> 10% of bladder cancers
7.2.5 Some Oncogenes produce intracellular protein kinases
 Serine/threonine kinases
----> Raf (A-Raf, B-Raf, C-Raf)
----> MEK (MEK1, MEK2)
----> MAPK or ERK
 Nonreceptor tyrosine kinases
----> Src kinase: intracellular
: SRC mutation (certain colon cancer)
: interacts with many growth factor receptors
----> Jak kinase: Jak-Stat signaling pathway
: TEL-JAK2 --- translocation chromosome 9 & 12
(certain leukemias)
----> Abl kinase: a cytoplasmic and nuclear protein tyrosine kinase
: implicated in processes of cell differentiation, cell
division, cell adhesion, and stress response.
 contribute to cancer development by stimulating pathways that
activate cell proliferation, promote cell survival, or both.
v-mpl ---> receptor
for Thrombopoietin
STAT=Signal Transducers
and Activators of
Transcription
7.2.6 Some Oncogenes produce Transcription factors
 Transcription factors = proteins that bind to DNA and alter the
expression of specific genes.
 Jun, Ets ----> stimulate the transcription of early genes that code
for other transcription factors (Myc, Fos, and Jun)
 Myc, Fos, and Jun ----> stimulate the transcription of delayed
genes
 E2F ----> one of delayed-gene products
 Myc ----> the most common oncoprotein detected in many human
and animal cancers.
: Burkitt’s lymphoma (chromosomal translocation) ---MYC
: small cell lung cancers (gene amplification) --- MYC, MYCN, MYCL
: breast and ovarian cancers (gene amplification) --- MYC
: neuroblastomas and glioblastomas (gene amplification) --- MYCN
 viral oncogenes
: c-fos, v-jun, v-myb, v-ets, and v-erb-a
7.2.7 Some Oncogenes produce Cell cycle or Cell death
regulators
 Cell cycle regulator genes coding for proteins involved in cell
proliferation.
: cyclin-dependent kinases (Cdks)
---> CDK4 (gene amplification in certain sarcomas and
glioblastomas)
: cyclins
---> CYCD1 (gene amplification in breast cancers and
chromosomal translocation in some lymphomas)
: such oncogenes cause the production of excessive amounts or
hyperactive versions of Cdk-cyclin complexes, which then
stimulate progression through the cell cycle.
 Cell death regulator genes coding for proteins involved in cell
death.
---> BCL2 (chromosomal translocation in non-Hodgkin’s
lymphomas) --- excessive amounts of Bcl2
---> MDM2 (gene amplification in some human sarcomas)
:BCL2 and MDM2 helps cancer cells evade the apoptotic
pathways