Oncogenes, TSGs and unrestrained growth -L3 Flashcards
What is a kinase ?
it is a protein that phosphorylates another protein target - addition of a phosphate group to other proteins can lead to activation
What are some examples of kinases ?
Receptor tyrosine kinase- present in the cell membrane and assesses the local environment. They can activate signalling cascades through phosphorylation
Cyclin-dependent kinase- they phosphorylate proteins when they are in a complex with a cyclin
What are growth factors ?
Poorly defined, larger heterogeneous group of molecules
Soluble ligands produced by one cell to influence another
Act at cell, tissue and systemic levels
They are not necessarily to do with growth
What are the 3 main functions of growth factors in relation to homeostasis?
HOMEOSTASIS- the balance between these factors tells the tissue it is ok
Survival Factors= nerve growth factor, they control cell numbers via a limited supply. If a cell doesn’t receive enough of these responses then it will initiate apoptosis
Growth Factors= TGF-alpha, stimulate growth when its necessary
Differentiation Factors= TGF-beta, reduce growth and stimulate terminal differentiation
In normal cells, cell number is tightly controlled by what processes?
Stem cell differentiation= asymmetrical division into a cell with a specific function and another stem cell
Proliferation
Programmed cell death
it is the balance between these 3 processes that maintains a consistent number of cells within a tissue
What are the different signalling methods that allow tissues to maintain normal cell numbers?
Regulated by local and circulating factors
Paracine signalling
- cell to cell contact= directly contacting cells will have proteins between them that can relate info
-growth factor capture= secretion of factors to bind to receptors upon cells
Endocrine signalling= hormonal signalling
How does paracrine signalling work ?
1) cells is either stimulated or inhibited by growth factors for cell division
2) once the grwoth factor has bound to the receptor the signal is transduced into the cell and relayed to the nucleus
3) then transcription factors are activated to either produce mRNA that promotes cell division or mRNA that inhibits cell division
What are the different processes for sustaining proliferative signalling ?
1) Autocrine regulation= cell releases a ligand that acts on itself
2) Disturbed Paracrine signalling= stroma/epithelial cell interactions
3) receptor dysregulation= overexertion of receptors leading to hypersensitivity. e.g. overexertion of receptor tyrosine kinase
4) ligand independence= mutation in the receptor so it doesn’t need a ligand to activate it because it is always active
5) Constitutive activation of downstream pathways- individual branches are activated= AKt
In abnormal cells what can happen between tumour cells and fibroblasts for example ?
paracrine signalling can occur between the tumour cell and the fibroblast because the tumour cell tells the fibroblast to produce GFs or stimulate energy requirements
What are the steps in overexpression of receptors ?
there is an increase in gene copy number
there is an increase in mRNA transcription
there is an increase in cell surface receptor protein expression - leads to hypersensitivity from the ligand
When mutations occur in receptors what happens ?
mutations can cause the receptor monomers to come together without activation by the ligand and therefore they are active all the time
e.g. EGFR in 25% of neuroblastoma
What can happen when a ligand activates EGF-R?
it recruits Sos Guanine exchange factor to RAS
- in normal tissue recruitment of Sod leads to activation by converting GDP to GTP
- in abnormal tissue the RAS can be mutated and it prevents the GTP being hydrolysed and this means it is active all the time
What makes the EGF-R even more complicated ?
the fact it is actually part of a family of 4 proteins that can form homo or heterodimers therefore there are multiple different forms
it can also be activated by many different molecules
What does EGF-R2/Her2 contribute to ?
overexpression of the receptors contributes to about 30% of breast cancers
How else can EGF-R also activate p13K?
it can activate it through RAS but it can also activate it directly
What are some examples of Ras genes and what are they the 1st signalling molecules of?
H-ras, K-ras and N-ras
they are the 1st signalling molecule downstream of receptor tyrosine kinase
What is the Ras oncogene?
it is a mutant form of the G protein Ras- very common in tumours
What does the Ras oncogene encode?
it encodes a protein with normal GTP binding but without GTPase activity so therefore it is always active
- this can lead to unregulated growth
What % of lung, colon and pancreatic cancers are associated with Ras mutations ?
lung and colon = 30-50%
pancreatic = > 90%
therefore Ras targetted drugs would be beneficial to the treatment of cancers, particularly for pancreatic
Summary of growth factors in cancer:
1) pathway is overactivated by several potential mechanisms
2) extracellular signalling and cell fate are developed by mutations in key genes
3) result is always the same; enhancement of proliferation
What are Cyclin dependent kinases (CDKs) required for ?
They are necessary for progression through mitotic checkpoints
What does elevated levels of GFs cause?
it results in abnormal progression through cell cycle checkpoints
What do mitogenic GFs do ?
They increase cyclin D expression levels
promote mitosis
What do negative GFs do ?
increases expression of key CDK inhibitors
e.g. P21- disrupts activity between cyclin dependent kinases and their kinases
How are different phases of the cell cycle regulated ?
different kinases bind to different cyclins to regulate the different phases
the levels of cyclins change
What is pRb and what does it do ?
retino blastoma protein - commonly mutated TSG in cancer
it binds to E2F and hides it preventing its entry to the nucleus
What is the E2F family?
They are a family of transcription factors - some activate transcription while others repress it
What are the pocket proteins of pRb?
p107 and p130- they look similar to pRb
What are nuclear receptors ?
they are a superfamily of ligand activated transcription factors e.g. oestrogen receptor and vit D receptor
What do nuclear receptors respond to ?
xenobiotics, metabolites, dietary factors and hormones
What effects upon proliferation do nuclear receptors induce ?
they can be either pro or anti-proliferative and their roles can change in a cell dependent complex
What do nuclear receptors do and what regulates them ?
they interact and modulate other growth signals
regulated by cofactors and by each other
can be unregulated in cancer
What are examples of nuclear receptors ?
Vitamin D receptor VDR
vitamin A receptor RAR
cholesterol/bile acids/oxysterols (LXR)
hormones AR, ER, PR
What do TSGs encode?
they encode proteins that normally restrain cell division and if mutations occur in these genes these restraints are removed
What are mutations in TSGs and what does it mean ?
they are genetically recessive
- this means that you need mutations on both alleles
- if you inherit one correct copy and one defective copy you will not be diseased
-
What does loss of heterozygosity mean ?
its when you develop a mutation in your good copy causing mutations in both alleles
- loss of the copy that was protecting you
What is p53 gene known as and why ?
known as the “guardian of the genome”
it halts cell division
How many cancers involve p53 mutations and what do they cause ?
half of all known cancers involve mutations in p53
- most other cancers will have mutations upstream or downstream of p53
mutations lead to half life extension
What actually is p53?
it is a transcription factor with more than 100 gene targets
What down regulates p53 at the protein level ?
down regulated at the protein level by Mdm2
What does Mdm2 do to p53?
as soon as Mdm2 binds p53 it degrades it - it regulates stability
in the absence of Mdm2 p53 is unregulated
What do many of the mutations in p53 mean ?
they mean that Mdm2 cant degrade it
What happens when p53 induces p21?
it prevents hyperphosphorylation of Rb which induces G1/S growth arrest- if this becomes irreversible (SENESCENCE)- the cell cant go through the checkpoints
When does senscence occur?
if the cell is maintained in arrest for too long
What can high levels of p53 induce ?
can induce apoptosis (via bax) in response to excessive levels of DNA damage
What happens when p53 is lost ?
it allows replication of damaged DNA, loss of apoptotic responses and lack of senescence
What happens in gain of function and loss of function mutations ?
GOF= mutation of a proto-oncogene into an oncogene
LOF= mutation in tumour suppressor gene
LOF are more common than GOF but there must mutations in both alleles
