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Molecular Biology of the Cell Chapter 20 Part 3

How mutations in cancer critical genes cause the 'misbehavior' characteristic of cancer cells and how the functions of these genes can be determined
STUDY
PLAY
1. Cell-cell communication,
2. Regulated cell growth,
3. Cell division,
4. Cell differentiation,
5. Cell death,
6. Cell movement,
7. Cell adhesion
Development and maintenance of a multicellular organism depends on numerous regulatory pathways. What are they?
Cancer cells
Cell-cell communication, regulated cell growth, cell division, cell differentiation, cell death, cell movement, and cell adhesion are misregulated in what kind of cells?
Mouse model systems
What kind of animal model systems do scientists use to introduce oncogenes, in order to understand their function?
Increase
Not all mice expressing a single oncogene acquire tumors. Does the combination of two oncogenes significantly increase or decrease tumor formation?
Additional accidental changes are required for tumor formation
Tumor formation takes time suggesting what?
The cancer critical gene
Tumor suppressor genes have also been studied by deleting the gene for what?
Yes
Will mice with a single copy of a tumor suppressor gene deleted accumulate cancerous tumors at a higher frequency?
Embryonic lethality
Deleting both copies of a tumor suppressor genes leads to what?
Growth, division and death
The 'normal' versions of cancer causing genes are involved in signaling pathways that regulate a cells 'social' behavior including what?
1. Transmembrane receptors,
2. Signaling proteins,
3. Intracellular GTP-binding proteins,
4. Protein kinases,
6. Gene regulatory proteins
Proteins encoded by proto-oncogenes and tumor suppressor genes include what?
Cell growth, DNA replication and cell division
Mutation of proteins encoded by proto-oncogenes and tumor suppressor genes disrupt normal signaling pathways creating proliferative signals to switch on what?
In the same signaling pathway
Often mutations in tumor suppressor and oncogenes have been found where?
Cell proliferation
Tumor suppressors normally function to inhibit what?
Cell growth/division
Proto-oncogenes function to promote what?
S phase
The Rb mediated pathway regulates cell entry into what phase?
An E2F family member
Active Rb protein binds to what to block expression of downstream genes?
S phase
Active Rb protein binds to E2F family members to block expression of downstream genes. These downstream genes encode proteins responsible for entry into what?
Unphosphorylated 'active' state
In nonproliferating cells, Rb is in its what state?
The p16 protein
In nonproliferating cells, Rb is in its unphosphorylated 'active' state through the activity of what?
Cdk4, a G1 cyclin dependent kinase
p16 binds to and blocks the kinase activity of what?
Cell cycle progression
p16 activity keeps Rb unphosphorylated thereby halting what?
Increases
When the cell receives the correct signals, what happens to the levels of active G1-Cdk?
Rb
When the cell receives the correct signals, the levels of active G1-Cdk increases leading to phosphorylation of what?
Inactive
Is phosphorylated Rb active or inactive?
The expression of genes needed for entry into S-phase
Phosphorylated Rb is inactive, releasing E2F proteins to promote what?
Rb or p16
Many cancer cells proliferate inappropriately by inactivating what?
p16
Deletion, inactivation or DNA methylation of what gene has been identified in human cancers?
Cdk4 or Cyclin D genes
Some glioblastomas and breast cancers have been linked to overexpression of what?
Rb and p16 genes
In the Rb pathway, tumor suppressor mutations have been identified in what?
Cdk4 and cyclin D genes
Oncogenes have been identified in what?
Continued cell growth
Survival of cancerous cells also requires what?
Smaller cells with each successive division
Cell cycle progression without cellular growth results in what?
Mitogen mediated signals and growth factor mediated signals
What are two types of extracellular signals required to drive a cell through the cell cycle?
Mitogen mediated signals
What signals are important for driving the cell cycle?
Growth factor mediated signals
What signals are required for the uptake and utilization of nutrients?
Inappropriate cell growth
Continued growth of a cancer therefore also requires heritable changes that induce what?
Extracellular signals
The PI-3 kinase/Akt intracellular signaling pathway is activated by what kind of signals: extracellular or intracellular (e.g. insulin and insulin-like growth factors)?
PI3 kinase
Activation of receptor tyrosine kinases activates what?
Akt
Activation of receptor tyrosine kinases activate PI3 kinase which in turn leads to the activation of what?
Protein synthesis is increased; Glucose uptake is stiumulated
Through its effect on mTOR, what is increased? What is stimulated?
Membrane biosynthesis
Through its effect on mTOR, protein synthesis is increased and glucose uptake is stimulated leading to increased what?
PTEN
In cancerous cells, tumor suppressor mutations have been identified in what?
A protein phosphatase
What is PTEN?
Dephosphorylating substrates phosphorylated by PI3 kinase therefore buffers Akt activity
PTEN is responsible for what?
Increased Akt levels
Loss of PTEN leads to what?
Hyperactivation of this signaling pathway
Loss of PTEN leads to increased Akt levels, which leads to what?
Glycolysis
Over stimulation of this pathway explains the observation that tumor cells exhibit increased rates of what?
High rates of glucose uptake coupled with high levels of pyruvate excretion
What is used to identify tumors?
Cell proliferation balanced by cell death
How is cell number maintained?
When they have sensed DNA damage or the absence of extracellular survival signals
When do animal cells undergo apoptosis?
Bcl2
What protein is normally involved in inhibiting apoptosis?
B-cell lymphoma
Inappropriate overexpression of Bcl2 (translocation event) is responsible for what
p53 (the cellular stress sensor)
What is another apoptosis control gene identified in cancer besides Bcl2?
Increases
In response to hyperproliferative signals, DNA damage, hypoxia, or telomere shortening, do the levels of p53 increases or decreases?
Mdm2 repressor binding
An increase in p53 is achieved through the loss of what?
Cell cycle arrest or apoptosis
Stable and activated p53 triggers the transcriptional activation of genes whose proteins are involved in what?
1. Stimulate the expression of pro-apoptotic genes
2. Binds to anti-apoptotic factors to block their activity
What are the functions of p53?
1. Loss of p53 allows cells to progress through the cell cycle with DNA damage,
2. Loss of p53 allows cells to escape from apoptosis,
3. Loss of p53 promotes genetic instability which promotes the accumulation of DNA
mutations,
4. Loss of p53 makes cells more resistant to anticancer drugs and irradiation
The loss of p53 promotes cancer for what 4 reasons?
The cell cycle or cellular apoptosis
DNA tumor viruses interfer with what?
Double stranded DNA viruses
What are capable of surviving in host cells as extrachromosomal plasmids that replicate along with the host cell chromosomes?
The papillomavirus
What is a DNA tumor virus identified as the causative agent of uterine cervical cancer
The basal layer of the cervical epithelia
The papillomavirus exists where?
Extrachromosomal plasmids
The papillomavirus exists in the basal layer of the cervical epithelia as what?
Benign growth or wart
A switch to a replicative phase (papillomavirus) occurs in the cells of the outer epithelium resulting in continued cell growth and the formation of a what?
The viral genes integrate into the host chromosome and become active within the basal layer (location of stem cells)
How can cancer result from a papillomavirus?
E6 and E7
What are two viral genes that are responsible for promoting (papillomavirus) cancer?
Viral proteins (E6 and E7)
What proteins can interact with many host cell proteins blocking their activity?
Tumor suppressor proteins
E6 and E7 bind to what?
Cell proliferation
E6 and E7 bind to tumor suppressor proteins to shut down their activity promoting what?
The host cell Rb protein
The viral E7 protein binds to what?
Uncontrolled DNA replication and cell division
E7 binding prevents Rb from binding to and inhibiting the activity of the E2F family of gene regulatory proteins leading to what?
The host cell p53 protein
The viral E6 protein binds to what?
Cdk activity and unchecked cell cycle progression
E6 binding triggers p53 protein degradation leading to an increase in what?
Uncontrolled growth
What is not sufficient for the progression of a cell into a cancerous state?
Tumor cells must escape their parent tissue, travel
through the circulation, and colonize a remote site
How does metastasis work?
No
Is the identity of genes whose mutations promote metastasis known?
The first step (local invasiveness) and the last step (colonization at a remote site)
What two steps are likely the biggest barriers to metastasis?