Transcript Oncogenes, Tumor Suppressors, and the Cell Cycle

Oncogenes, Tumor Suppressors,
and the Cell Cycle
Radiobiology
2012
Cancer is consequence of
abnormal increased cell growth
and/or decreased cell death
• Normal tissue homeostasis balances cell
growth and death to maintain constant mass
• Normal tissue hypertrophy can come from
increased cell number (pregnant uterus), or
increased cellular mass (exercising muscle)
• Normal tissue regeneration can be
physiologically necessary (bone marrow, gut
epithelium, skin) or in response to damage
(liver regeneration)
Cancer cell dynamics are not under
normal processes of cell control
• Oncogenes (activated proto-oncogenes) are
generalized as drivers of tumor cell division
• Tumor Suppressors are generalized as brakes
to cellular division
• Therefore oncogenic transformation combines
activation of proto-oncogenes and loss of
tumor suppressors to drive cell proliferation.
Impact of Transformation on the
Cell Cycle
Many physical and chemical insults can
activate a proto-oncogene
Several Molecular Mechanisms
to activate a proto-oncogene
Cytogenetics identified the
“Philadelphia Chromosome”
Peter Nowell at Penn
Found a small Ch22
in patients with CML
Identification of
activated oncogenes
experimentally
H-ras V12D identified in 1983
Cell Fusion Identified the concept of
“The Tumor Supressor Gene”
Cancer Cell
PEG or Virus
Normal Cell
Heterokaryon has more “Normal”
Cellular phenotype
Some normal gene was lost in cancer cell?
Tumor Suppressors require
“Two-Hit” inactivation
One allele
may be lost
in the germ line
LFS can result in many types of cancer
Cancer Predisposition Syndromes helped
identify Tumor Suppressor Genes
Loss of Heterozygosity can Remove the
Normal allele and result in functional loss
How do Oncogenes and tumor
suppressor disrupt normal functions?
• Ocogenes:
– Stimulate the cell cycle (ras)
– Inhibit death (Apoptotic) signalling (bcl2)
– Drive metastatic growth (Met)
• Tumor suppressors
– Release brakes in the Cell Cycle (p53/Rb)
– Release brakes on growth factor signals (PTEN)
– Modulate response to stress (VHL)
– Increased survival signals (APC)
Function of oncogenes in normal
growth signal processes
Function of oncogenes in blocking
normal death signals
MYC can drive several processes
Cancer is a multi-step process
Colon Cancer Moleculr Oncogenesis – Vogelstein and Kinzler
“Mutator” phenotype can accelerate
Multi-Hits needed for Transformation
DNA metabolism obiously important to maintain integrity of the genome
Metastatic spread requires additional
genetic changes
Senescence can also block cellular
transformation
Normal fibroblasts
Have finite number
Of divisions before
Permanent Arrest
Genomic Instability can accelerate
Tumor formation
• DNA damage can be:
– Properly repaired without consequences
– Non-repaired that can lead to cell death
– Mis-repaired contributes to alterations in gene
sequence or expression
Radiation Response impacts
the Cell Cycle Machinery
G1 Arrest
After XRT
Deckbar et al
Crit Rev Biochem
2011
G2/M arrest after XRT
Deckbar et al
Crit Rev Biochem
2011
DNA Repair–Deficiency can result in
tumor predisposition
Loss of ATM predisposes to Radiationinduced Cancers
Mutations in Mismatch Repair genes
causes Predisposition to CRC
Radiation also impacts
Lipid Second Messenger Signaling
Fuchs and
Kolesnik model
NF-κB pathway is also
Stress-Responsive
Pro-Survival
Signals
Aid
Tumor Cell Growth
Summary
• Cancer is a multistep process
• Gain of oncogenic function or loss of tumor
suppressor function impacts many cellular
processes (cell cycle, apoptosis, senescence)
• Some genetic events that contribute to cancer
formation can also influence response to DNA
damage dependent therapy