- Information
- AI Chat
Cell Proliferation
Medicine (A100)
Keele University
Preview text
Cell Proliferation: - Basics of cancer progression - Increase in cell number – requires a cell to grow in size to be divided into two daughter cells, which also then grow - Essential for homeostasis – some cells die so need to synthesise more. - Deregulation (increase in drive to proliferate, which can cause cancer) or apoptosis (lead to degeneration of cells) can result in cancers and neurodegeneration.
(Mitogens = drive proliferation)
Control of normal cell proliferation: - Cells don’t just proliferate; they only divide and increase in numbers when more cells are needed. - Mitogens e. growth factors or cytokines send signals from outside the cell which cause the cell to proliferate and divide. - Normal cells can’t divide unless they are able to pass the restriction point (R-point), which is at the end of the G1 phase. The restriction point blocks cells from moving from G1 to the S phase where DNA replication occurs. Before a cell undergoes cell cycle, it must ensure the conditions are correct for the cells to divide - A mitogenic signal causes the cell to synthesise proteins which allows the cell to overcome the break and move into the S phase.
Key concepts in mitogenic signalling: 1. Cells receive signal in the form of a mitogen (acts as a ligand) which binds to the receptors on the plasma membrane. 2. Receptors become phosphorylated/activated and relay signals which causes cascades of intracellular signals. 3. This then activates transcription factor which activate genes that codes for the protein which will help overcome the R-point.
Mitogen Activated Protein Kinase (MAPK): 1. The binding of mitogens activates RTK (Receptor Tyrosine Kinase), which relay the signals inside the cells and turn on GTPase Ras. 2. MAPK signalling cascades act as modules to sustain the signal intracellularly -they have kinase activity and relay the signal by phosphorylating proteins. 3. MAPKs can activate or function as transcription factors (TFs) and direct the cellular response. 4. Transcription factors bind to DNA and allow the transcription of genes and hence expression of proteins to match the demand of the signal for cell proliferation.
The 3 proteins of each of the cascade are all kinases. Each of the cascade is known by the final kinase e. ERK pathway, p38 pathway, JNK pathway
ERK Pathway (Extracellular-signal Regulated Kinase): - Historically, it was thought just to be about cell proliferation but it was found to contribute in other cellular responses such as differentiation.
EGF pathway: 1. EGF (acts as a mitogen) is released by macrophages which stimulate epithelial cells to divide and proliferate which is important for wound healing. 2. EGFs bind to the EGF receptors (EGFR) which leads phosphorylation of the receptor, causing it to be activated. 3. Once EGFR is activated, it relays the signal inside the cells by phosphorylating other proteins including Grb2 and SOS 4. SOS activation in turn allows it to activate Ras. 5. Ras is a g-protein, which is structurally similar to the Ga subunit of heterotrimeric G-protein 6. Ras is a small GTPase which is activated when GTP bound Raf through the action of SOS (which belongs to the family of GEF). GAPS turn Ras OFF. 7. Active Ras attracts Raf to bind it, which allows it to become phosphorylated and activated. 8. Since RAF is a kinase, it phosphorylates MEK. 9. Phosphorylated MEK relays the signal by phosphorylating ERK. 10. MEK is the only protein that acts on ERK which is a multifunctional protein. Activates AP-1 which activates expression of genes required of the cell cycle progression.
Raf is an isoform (structurally similar, but very different in HOW they activate MEK and to what degree) and comes in 3 forms (A-Raf, B-Raf and C-Raf).
MEK is the only protein that acts on ERK which is a multifunctional protein. Activates AP-1 which activates expression of genes required of the cell cycle progression.
EGF → EGFR → Grb2 → SOS → Ras →Raf MEK ERK →AP-1 = Normal
Cells can maintain normal cell proliferation: 1. After activation, the proliferative signalling is turned off. 2. Must be able to die when required (induce apoptosis)
Turning off mitogenic signalling: 1. Prevent release of Ligand (EGF) EGF is normally synthesised as a transmembrane protein (sits on the membrane) Metalloproteinases (scissors) – able to cleave off EGF so no longer bound to cell membrane, making it no longer soluble so can diffuse and bind to the receptors. Can reduce metalloproteinases (mutations) so won’t have any EGF release
- When cells incur DNA damage, a signalling cascade is initiated which leads to the phosphorylation of p53.
- Phosphorylation of p53 prevents mdm2 from binding to p53, blocking its degradation.
- P53 levels accumulate and is able to mediate DNA repair or activate apoptosis
Puma (P53 Unregulated Modulator of Apoptosis):
- An apoptotic stimulus causes the activation of p53 which provokes expression of PUMA (p 53 upregulated modulator of apoptosis) which activates Bax and Bak.
- Bax and Bak are two major pro-apoptotic proteins.
- The activation of Bax and Bak induces them to form pores in the mitochondrial membrane to allow the release of cytochrome c.
- This then triggers the activation of caspases and apoptosis.
- Anti-apoptotic proteins (survival factors) inhibit apoptosis. Bcl2 and BclXL are two major anti-apoptotic proteins which bind and block the action of Bax and Bak.
Caspases: - Intracellular proteases which are able to cleave different kinds of protein. - Synthesised as inactivated caspases – procaspases - Procaspases are converted into active caspases only during apoptosis.
Apoptosis and Cancer: - Natural barrier in preventing cancer development. - p53 is responsible for the expression and activation of pro-apoptotic proteins (Puma, Bax and Bak) - Thus, cells incurring significant DNA damage are eliminated through the function of p53 and Bax/Bak in activating apoptosis. - However, cells with non-functional p53 will not activate Bax/Bak and less likely to undergo apoptosis. This results in the survival of a genetically unstable cell which could then develop into a cancerous cell.
Cell Proliferation
Module: Medicine (A100)
University: Keele University
