LMP299Y1 Lecture Notes - Tumor Suppressor Gene, Receptor Tyrosine Kinase, G1 Phase

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3 Jun 2013
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Cancer Genetics molecular bases March 26
Determination of cell needs to prolifeate and divide
Signal transduction crucial to all cells a number of ways to stimulate cells to grow
Signal transduction relay message through cell received on surface of cell send signal to nucleus
theme for many pathways
RAS binds nucleotides bound in inactive form to dinucleotide; when activated, bind GDP when
trigger RAS, it mediates whole signalling cascade not requiring anything from outside of cell when
trigger RAS, signal on route to get to nucleus
RAF1
If xternal factor present, signal relayed
If not growth factors available or receipient ligands no message relayed
Key things to remember for pathways and how to deal with external cues some conflicting, some
driving forward lots of components and steps many proteins in canonical pathway that are members
of same gene family different members can respond can have intricate response to various external
stimuli one cell can have different receptors and respond to different stimuli
Can lead to cancer in different organs depend on where expressed
Players that can act in others one such is MYC (important!)
If can get to nucleus and drive the program that says to proliferate without having received external
signal
ABL gene not receptor tyrosine kinase
Examples of genes that when mutated, act as onocogenes so promote development and progression of
cancer***********
Oncogenes in process of cell division generally tigtly controlled process but this can be disregulated
lead to inappropriate growth or cell division in normal circumstances lead to cells growing
inappropriately when in normal situations, they would not growth regulating signals that can be
coming from external cues could be signal transduction process act on cells from outside and
stimulate cell into cell cycle ultimately, there is coordination of events cell division not cell
proliferation cell division is cell dividing itself, not the same as cell receiving signal to grow recognize
cell cycle with a number of check points
Three cycle chekcpoitns
G1 phase at this point where the cell is still receving signal from outside but pass this point, cell will
make decision to divide regardless of external cues
Later checkpoitns important for cell checking all DNA is properly divided; environment enough space for
diviing cell
Transition from G1 to S phase of the cell cycle
Interreleated pathways look at what drives cell signalling variety of genes involved and some key
players are cyclins
Cell cycle genes have had multiple renditions of naming
G1 to S phase major inihbiitso to cell cycle p15, p16, etc
Another aspect of cell cycle G1 S checkpoint primary
CLNE PCNA activating to allow E2F to get to nucleus to tell cell to divide
All components that work together also a variety of inhibitors important to contributing and putting
brakes on inhibitors responses to diferent things including recognition that there is problem ith DNA
DNA damage and there isn’t time there has not yet been time for DNA to repair the idea of
monitoring and checking DNA damage is ongoing these inhibitors can come and work on the
checkpoints to tell the cell cycle to halt the cyclins are also fairly tightly regulated
Apoptosis
If disregulate this process or take it away and block apoptosis
P53 is major tumour suppressor gene will repress the BCL2 gene and if the BCL2 gene concentration is
decreased lead to apoptosis cause increase in transcription of BAX gene, which if increased lead to
apoptosis BAX contributes to stimulating apoptosis and BCL2 will inhibit it if increase amount of BCL
2 will increasingly inhibit process BCL2 is common onco-gene in some types of cancer causes bypass
of apoptosis one and a few examples of how you can hijack the apoptosis cell process such that the
cell will grow inappropriately even under severe stress situations apoptosis is one of variety of
responders of cells releated and overlap one pocess is autophagy
Autophagy is survival process that can also elad to cell death all the organelles gotten rid off
Autophagy does play a role in cancer cells that are deficient in some of the genes that play role in
autophagy one such example is beclin which even in heterozygous state, increases susceptibility to
cancer in aptoptosis-0related process
Oncogenes in development of cancer is in metastasis in cancer, genes that can contribute to initation
and promotion more seriously to concern that cells can start to spread generally, late stage of cancer
depending on cancer type cell become migratory and evasive first day of cancer properties of
transformed cells loses sense of cell contact seriously concern of clinical standpoint because hard to
tackle if able to move around variety of process that can contribute to particular event one such
process in many kinds of cancer is EMT transition
EMIT transition with epitheial cancers in metastasis
Promotion of tumour metastasis
If lose e-cadherin lose junctions between cells variety of changes can happen in cell that lead cell to
change shape and capacity to invade and moe around one possible type protein other protesins are
matrix proteinase proteins of intracellular matrix if increase activation of proteinase, extracellular
matrix where lots of proteins are present digesting away proteins a llow cells to have some migration
ability escape from primary site crucial also affect metastasis by inhibiting some of the proteases
may well allow protease to act when it shouldn’t – render cell able to move away from particular
llocation very problematic
Alternations and mutations in are specific alterations in genome that cause or the consequence of
cancer development cause genes to change to have different properties oncogenes and tumour
suppressors appreaciate from description think of oncogenes, acquire gain of function changes
that give perpetual function or prolonged function or increased function mutations that involve gain of
function or increase their levels or express them where not ordinarily expressed oncogene function
genes that prevent cell proliferation or that activate apoptosis or related properties carry loss of
function mutations also genes that help and are involved in DNA damage that when mutated, will lead
to increased mutation rate and contribute to genome instability crucial to development of cancer
Many types of changes that can occur most know today is for most changes, need number of changes
Cancer diseas of old age ongoing change!! one of the features that contribute to cancer being
disease of older age
Genetic susceptibility already have change in the genome these can occur in oncogenes or tuour-
suppressors
Role for stem cells for cancer this is probably true in hematopoeit and some blood cancers, the
concerning cell is rogue stem cell, a CANCER STEM CELL features of stem cell, protected in body
properties of stem cells contirubte to why they are dangerous
Stem cells sensitivie to apoptosis if bypass aoptosis (ex. Take out p53) cell becomes rogue, cannot
sense if there is a problem
Hard to find, hard to recognize
Efflux pumps if in mixture of stem cells, mature cells see lots of cancer mature cells, can pump in
drugs, cancer stem cells with high levels of efflux pumps can pump out the drugs
Hemopoietic stem cells in bone marrow heavily protected
Not all cancers have stem cells but in some cancers, here are cells with stem cell like properties
Tissue organization and protection of the stem cell genome