The Cell Cycle

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The Cell Cycle

• Positive extracellular controls
• Stimulation of cell division by mitogens (ptn
  ligands released by neighboring cells)
• EGF epidermal growth factors work through RTK
  action

• Negative extracellular controls
• Secreted ligands like TGF-b are negative growth
  regulators
• Target SMADs and keep Rb/E2F complex intact

2
Apoptosis

• Positive extracellular controls
• AB producing B and T cells only a small
  fraction are actually functional (immature cells
  must be eliminated)
• Fas and FasL Fas from one cell binds to Fas
  ligand on adjacent cell, trimerizes cytoplasmic
  domains and activates caspases (Apaf) leading to
  cell death..see Fig. 22-15.

• Negative extracellular controls.
• These exist as survival factors and are
  potentially dangerous (but not well
  characterized).

Key message Intercellular signaling cascades
communicate whether to proliferate or destruct.
The balance is absolutely critical in normal
tissue function.
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Cancer Genetics The big picture
Events INSIDE cells but also with neighboring
cells are important
4
Cancer cells look and behave differently from
normal cells
Transformed 3T3 cells No growth arrest at
confluence cells pile up
Normal 3T3 cells Growth arrest at confluence
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Cancer has a genetic basis

• Can be inherited but generally due to mutations
  in regulatory circuits (involve oncogenes and
  tumor supressor genes).
• Is a multi-hit process (requires more than a
  single mutation).
• Tumors are clonally derived

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Mutations in cancer.

• Oncogenes.
• Dominant since one allele is activated and
  imposes its will on cell.
• Heterozygous
• Increase rate of growth
• Growth control is deregulated
• Gain of function mutations
• Tumor promoting alleles

• Tumor suppressor Genes
• Mutations inactivate them
• Requires loss of both alleles therefore its a
  recessive mutation (homozygous).
• These mutations tend to reduce chances of cell
  suicide (apoptosis)
• Why deleterious?
• Cells do not apoptose, leads to longer lifetime,
  greater chance for mutations.
• Changes associated with tumorigenesis should
  induce apoptosis.

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Oncogenes

• More than 100 identified.
• Normal counterpart proto-oncogene.
• Role of proto-oncogenes activate cell growth in
  response to PROPER stimulation. For example
• -Some are cc positive elements growth factors
  and their receptors, signaling pathway elements.
• -Others function to negatively regulate apoptosis
  and cell death.
• In all cases oncogene mutations uncouple
  regulation of functions that control activity.

Types of oncogene mutations Point mutations,
loss of ptn domains and gene fusions
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• Point mutations
• Simple point mutation in a key regulatory domain
  can be devastating (see 22-19).
• Mutate gly to val at codon 12 creates an
  unregulated (on) Ras in bladder cancer.

• Loss of ptn domains.
• Deletions can remove key regulatory domains.
• EGF receptor (gene is v-erbB) if the
  extracellular domain deleted, it can dimerize
  without EGF Ligand
• Constitutively onalways driving signal
  transduction paths in absence of regulatory
  signals

10
Gene Fusion New combinations of genes and cancer
Philadelphia Chromosome in CML cloning and
sequence data reveal a translocation between
chromosome 9 and 22 cause fusion of two new gene
products bcr1 and abl. -abl is a
proto-oncogene encoding a cytoplasmic tyrosine
ptn kinase -When fused to bcr1 an activated
(deregulated) tyrosine kinase results that is
responsible for the uncontrolled growth of
leukemic cells.
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Gene Fusion New combinations of genes and cancer
Some translocations can disrupt gene expression
of oncogenes up regulation. In lymphoma an
enhancer translocates to activate bcl2 gene in B
lymphocytes -This gene should be OFF in B cells
overexpression has consequences. -bcl2 is an
anti-apoptotic ptn and promotes extended
survival of B cells (that should be targeted for
destruction).
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Tumor suppressor genes

• Negative regulator of the cell cycle Rb
• Another example TGF-b, Ligand that is a
  negative regulator of cc. Secreted from resting
  cells, binds receptor, activates kinase cascade
  and detunes Rb phosophorylation

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Disease in children retinoblasts in adults
differentiate and no longer form tumors. In
young, these undifferentiated retinoblasts should
terminate growth..unless Rb is mutated.
wt
Sporadic cases of retinoblastoma involve at
least TWO mutations in the Rb gene.This is
Knudsons Hypothesis of a tumor initiation and
promotion. -Recessive homozygous situation
(essentially loss of heterozygosity or LOH) leads
to a situation where Rb is not active. Cells
lacking Rb (no functional Rb), especially
immature retinoblasts are destined for
transformation into tumor cells.
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Hereditary binocular retinoblastoma a germ line
mutation makes a 2nd mutation to homozygous
recessive much more likely. Absence of Rb means
that no active Rb gene product, means that E2F is
always free to activate S phase events. No growth
arrest in G1!
wt
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p53 Guardian of the genome and molecule of the
year 1993
Key features of p53 Tumor suppressor gene Mutated
in MANY cancers Mutant p53 more aggressive and
therapy resistant tumors Txn regulator turn on
after DNA damage Does two things 1)
checkpoints cc to allow time for repair of DNA
damage 2) In some cases induces apoptosis p53
negative cells dont do 1, 2 above which leads
to elevated mutations, translocations and
aneuploidy. Also, p53 nulls are prone to not
being culled by apoptosis. Tumor suppressor
genes if mutated may promote cc or block
apoptotic death.
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A good overview of mutations that lead to cancer.