Transcript Transcription factors

BioSci 145A Lecture 18 - Oncogenes and Cancer
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Topics we will cover today
– Oncogenes and cell growth
– tumor suppressor genes
– Important examples of transcriptional regulation
• Regulation of xenobiotic metabolism
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Last year’s final exam is posted
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No lecture on 3/12
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We will review last year’s final exam and I will answer
any and all questions on 3/14
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evaluations will be done on 3/14 as well so please come
and give us your candid assessment of the course
BioSci 145A lecture 18
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©copyright
Bruce Blumberg 2000. All rights reserved
Oncogenes and cell growth
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Seven classes of proteins control cell growth
– Collectively, these genes comprise the known set of
genes involved in tumor formation
BioSci 145A lecture 18
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©copyright
Bruce Blumberg 2000. All rights reserved
Oncogenes and cell growth (contd)
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BioSci 145A lecture 18
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©copyright
Dominant
transforming
oncogenes are
frequently created
from proteins
involved in
regulating cell
growth
– Growth factors
– Growth factor
receptors
– Intracellular
transducers of
above
– Transcription
factors that
mediate the
terminal effects
of extracellular
signaling
Bruce Blumberg 2000. All rights reserved
Oncogenes and cell growth (contd)
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Growth factors - proteins secreted by one cell that act on
another cell (eg sis, wnt, int)
– oncoprotein growth factors can only transform cells
that harbor the specific receptor
Growth factor receptors - transmembrane proteins that
are activated by binding to extracellular ligand (protein)
– very frequently protein tyrosine kinases
– oncogenicity usually results from constitutive
(ligand-independent) activation
Intracellular transducers - several classes
– protein tyrosine kinases, e.g. src
– G-protein signal transduction pathways - primary
effectors of activated growth factors (e.g. ras)
– protein serine/threonine kinases (e.g. mos, raf)
Transcription factors - these regulate gene expression
directly
– myc - HLH protein
– fos, jun - b-ZIP proteins
– erbA - nuclear receptor
common feature among these is that each type of protein
can trigger general changes in cell phenotypes by:
– initiating changes that lead to cell growth
– respond to signals that cause cell growth
– altering gene expression directly
BioSci 145A lecture 18
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©copyright
Bruce Blumberg 2000. All rights reserved
Oncogenes and cell growth (contd)
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One example signaling pathway - MAPK (Bardwell lab)
growth factor
receptor tyrosine kinase
ras
kinase cascase (serine/threonine)
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transcription factors
since the signal passes from one component to the next,
inappropriate activation of one element in the cascade
canl lead to widespread changes in gene expression
– these pathways are not strictly linear but branch and
interact with many other signaling pathways
• can cause wider effects
• may require mutations in parallel pathways to
get oncogenesis
central importance of this pathway is illustrated by the
number of components that can be mutated into
oncogenes
– aberrant activation of mitogenic pathways can
contribute to oncogenicity
BioSci 145A lecture 18
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©copyright
Bruce Blumberg 2000. All rights reserved
Oncogenes and cell growth (contd)
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Growth factor receptors are ligand modulated dimers
– EGF receptor (v-erbB) is the prototype member
• EGF binding stimulates dimerization and
activates tyrosine kinase cascade
• one oncogenic variant can dimerize in the
absence of ligand and signals constitutively
• another lacks an internal regulatory domain
resulting in constitutive signaling
– activated kinase domain autophosphorylates and can
then interact with src family proteins
BioSci 145A lecture 18
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©copyright
Bruce Blumberg 2000. All rights reserved
Oncogenes and cell growth (contd)
• transforming activity of
src-family kinases is
related to kinase activity
– autophosphorylation
controls activity
• Y416 -> active
• Y527 -> weak,
normally
suppresses
phosphorylation
of Y416
– some oncoproteins
activate src by
interfering with
phosphorylation of
Y527
BioSci 145A lecture 18
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©copyright
Bruce Blumberg 2000. All rights reserved
Oncogenes and cell growth (contd)
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modulation of transcription factor activity is important
for oncogenesis
– can’t cause cancer without altering gene expression!
BioSci 145A lecture 18
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©copyright
Bruce Blumberg 2000. All rights reserved
Oncogenes and cell growth (contd)
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transcription factors and cancer
– several prominent families of oncogenes are
transcription factors - rel, jun, fos, erbA, myc, myb
– actions may be quantitative or qualitative
• effects may be to increase activity of the
oncoprotein
– increased expression could upregulate target
genes and influence growth, e.g. AP-1
• alternatively, the mutations could make the
oncoprotein a dominant negative inhibitor of other
cellular transcription factors (e.g. v-erbA)
– many members are “immediate early” genes
• transcription is immediately upregulated without
the requirement for new protein synthesis when
cells are treated with mitogens
– likely to be involved with initiating or
promoting growth
• increased activity would be expected to increase
oncogenesis and it does with some but not others
BioSci 145A lecture 18
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©copyright
Bruce Blumberg 2000. All rights reserved
Tumor suppressor genes
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oncogenesis is not
typically dominant.
A growing number of
“tumor suppressor” genes
have been identified that
confer a genetic
predisposition to cancers
– several types of
genes are involved
• apoptosis
proteins (eg p53)
• cell-cycle
control proteins
(RB)
• DNA-repair
proteins (p53)
– classic examples are
RB (retinoblastoma)
and p53
– loss of tumor
suppressor genes is
implicated in several
infrequent cancers of
childhood
• retinoblastoma
• Wilm’s tumor
BioSci 145A lecture 18
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©copyright
Bruce Blumberg 2000. All rights reserved
Tumor suppressor genes (contd)
• RB is a nuclear
phosphoprotein that
influences the cell cycle
– unphosphorylated
RB prevents cell
proliferation by
binding to E2F and
blocking G1/S
transition
– phosphorylation of
RB inhibits binding
to E2F and releases
block
– some oncogenes (e.g.
SV40 T-antigen,
E1A) function by
sequestering RB and
removing block to
cell growth
– similar effects by
loss of both alleles in
human disease
BioSci 145A lecture 18
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©copyright
Bruce Blumberg 2000. All rights reserved
Tumor suppressor genes (contd)
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A variety of other cell-cycle control proteins are tumor
suppressor genes
– p16, p21 and D cyclins
– shown by identification of inactivating mutations in a
variety of human tumors
in quiescent cells
– RB is not phosphorylated
– D cyclin levels are low or absent
– p16, p21 and p27 prevent activity of cdk-cyclin
complexes
• cdc2, cdk2 and cdk4,6 interact with cyclins and
promote cell cycle
• this is blocked by tumor suppressor genes
BioSci 145A lecture 18
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©copyright
Bruce Blumberg 2000. All rights reserved
Tumor suppressor genes (contd)
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P53 suppresses cell growth or triggers apoptosis
– more than 50% of human tumors have lost p53
protein or harbor mutations in the gene
– a variety of mutations are possible
• recessive mutations cause loss of p53 function
allowing unrestrained growth (eg. ko mice)
• others are dominant negative p53 mutants that
interfere with normal p53 subunits in cells and
allow unrestrained growth (eg rare cancers)
BioSci 145A lecture 18
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©copyright
Bruce Blumberg 2000. All rights reserved
Tumor suppressor genes (contd)
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BioSci 145A lecture 18
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p53 has dual functions
– cells normally have
low levels of p53
– DNA damage induces
large increase in p53
levels
– increased p53 leads to
growth arrest until
DNA is repaired if
cells are in G1
– cells in S-phase or later
are triggered to
become apoptotic
p53 is a transcription factor
that typically activates
– one target is p21 ->
cell cycle arrest
– another is GADD45 - a
DNA repair protein
– role in inducing
apoptosis is unknown
at present
apoptosis is an important
pathway in preventing
tumor formation - blocking
it is a common strategy
©copyright
Bruce Blumberg 2000. All rights reserved
Cancer - putting it all together
BioSci 145A lecture 18
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©copyright
Bruce Blumberg 2000. All rights reserved