Flashcards in Oncogenes, TSGs and unrestrained growth -L3 Deck (47)
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
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
- 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
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