7: External Factors Flashcards
What are the types of external growth factors in controlling cell division?
- Growth factors
- Cell-cell adhesion
- Cell-ECM adhesion
How does Cell-ECM adhesion affect cell behaviour
- Cells required to be attached to ECM to begin protein synthesis and proliferation; the presence of GFs alone is not sufficient
- Cell phenotype can be determined by composition of ECM
- Cells also have adhesion molecules which have specific receptors for ECM molecules.
- There is mechanical continuity between ECM and cell interior (integrins)
What are integrins and how do they control cell signalling
Heterodimers (alpha and beta subunits)
Matrix-binding head regions (ligand binds between 2 heads)
Leg regions spans the plasma membrane
Different combinations of alpha/beta subunits bind to different ECM ligands
Link to actin cytoskeleton via actin-binding proteins
Outside-in signalling = ECM ligand binding to integrin complex can produce a signal INSIDE the cell therefore environment affects inside of cell.
Inside-out signalling = signals from inside cell can affect AFFINITY of integrin complex
Low affinity = bent
High affinity = Extended, legs open, greater recruitment of cytoplasmic signalling molecules
How does cell population affect cell division?
High density of cells = competition for GFs so less proliferation
How are GFs and the ERK cascade involved in cell proliferation?
GF -> grb2 -> adapter protein -> ras -> raf -> MEK -> ERK -> gene expression -> proliferation
GF Density Dependence
High density of cells = competition for GFs so less proliferation
Low density = no competition so cells PROLIFERATE
What is anchorage dependence and how is it involved in cell proliferation?
Anchoring to ECM via integrin promotes cell prolferation because GF receptors and integrin complexes can activate the same pathways
But only activation of BOTH receptors makes activation strong and sustained, otherwise its weak
What are the 2 types of contact interactions?
Contact interactions:
Short term = transient cell-cell interactions, doesn’t form stable cell-cell connection
Long term = stable cell-cell interaction, forms cell-cell junction
Explain cell-cell interactions in non-epithelial cells
Non-epithelial cells do NOT form stable junctions on contact but they repel themselves and move away from each other
This is called contact inhibtion of locomotion and prevents multilayering
Explain long-term cell-cell contact
Some cells adhere strongly on contact
This occurs in epi/endothelial cells which form layers
How does cell-cell adhesion affect cell division?
Cell-cell junctions form, inactive ERK cascade, increased p27KIP1, so LOW PROLIFERATION
What causes Adenomatous Polyposis Coli?
Degradation of beta-catenin leading to high proliferation
Explain the role of beta-catenin
Beta-catenin = bound to cadherin as part of adhesion complex but can also act as TF
In cytoplasm if APC complex is active it is degraded
If APC complex is inactive, it binds to LEF-1 and goes to the nucleus where it alters gene transcription leading to cell proliferation
So if there is a loss of cadherin-mediated adhesion or there is inhibition of degradation of beta-catenin you will get INCREASED proliferation
Explain why signaling pathways involving growth factors are often implicated in the uncontrolled division of cancerous cells
Because a lot of the components involved in GF pathway are proto-oncogenes which can mutate and become constitutively active leading to uncontrolled proliferation
Ras is mutant in around 30% of ALL cancers
How does a primary carcinoma cell metastasise?
Cell-cell adhesion must be down-regulated (reduce cadherins)
Cells must be motile
Degradation of ECM
Degree of cell-cell adhesion is an indicator of how differentiated and invasive primary tumour is.
