Cell Proliferation I Flashcards
What do cells need to pass in order to proliferate?
Restriction point (R-point)
What is the R-point?
What does it act as?
Restriction Point
Acts as a cellular brake, which blocks cells advancing from G1 to S-phase.
What are proliferative signals in the form?
Mitogens
What does a mitogen do?
Causes cell to synthesise proteins to overcome R-point
What is MAPK?
Mitogen Activated Protein Kinase
It is a signalling cascade
How do MAPK signalling cascades operate?
They operate downstream of many Tyrosine Kinase Receptors (RTKs) like EGFR
ERK pathway (MAPK)
Raf
MEK 1/2
ERK 1/2
p38 pathway (MAPK)
TAK
MKK 3/6
p38
JNK pathway (MAPK)
MAP3K
MKK 4/7
JNK
What is the ERK pathway commonly activated by? (2)
- mitogens
- growth factors
What are the p38 and JNK pathways activated by? (3)
- cytokines
- osmotic stress
- DNA damage
What is Ras?
G-protein
What are Grb2 and Sos?
Guanine exchange factors (GEFs)
Function of GEF (3)
- activate G-proteins
- by releasing GDP
- and adding GTP
How does a mitogen outside the cell tell it to divide? (5)
1) receptor activation leads to Ras activation
2) active Ras attracts Raf to bind and become activated
3) Raf phosphorylates and activates MEK
4) MEK phosphorylates and activates ERK
5) action of ERK controls activation of protein and transcription factors
How do cells maintain rate of cell proliferation? (2)
- after activation, cells need to turn off proliferative pathway
- cells need to be able to die when required
How is mitogenic signalling turned off? (2)
- prevent release of ligand
- turn off receptor
How is the release of ligand (EGF) prevented? (2)
- EGF is a transmembrane protein
- metalloproteinases cleave off and make EGF diffusible
How is the receptor (EGFR) turned off? (3)
- cells internalise RTKs (EGFR) and send it to lysosomes to be destroyed
- EGFR is tagged with ubiquitin
- to be marked for endocytosis and degradation
How does EGFR cause cells to proliferate? (9)
1) EGF binds to EGFR
2) EGFR is phosphorylated and relays signal
3) EGFR activates Grb2 and Sos
4) Sos activates Ras
5) active Ras attracts Raf to bind and become activated
6) Raf phosphorylates and activates MEK
7) MEK phosphorylates and activates ERK
8) ERK activates proteins and transcription factors
9) AP-1 transcription factors are activated to express genes needed for cell cycle progression
Function of Cbl
Functions in the endocytosis of signalling recpetors
Explain how Cbl mutation leads to cancer (4)
- endocytosis is required to turn off RTKs (like EGFR)
- Cbl mutation causes defect in the process of endocytosis
- this causes EGFR to remain active and continue proliferative signalling
- enabling cells to divide and proliferate uncontrollably (cancer progression)
What is B-raf and its function? (2)
- subtype of Raf
- relays signal to MEK
Explain how B-raf mutation leads to cancer (5)
- B-raf undergoes gain of function mutation
- this allows B-raf to be active without any mitogenic signalling
- hence continuous signalling relayed to MEK and ERK causing continuous activation of transcription factors
- causing continuous expression of proteins involved in activating the cell cycle
- hence hyper proliferation and cancer
Apoptosis
programmed cell death
What does p53 act as?
Transcription factor
Function of p53 (3)
- induce cell cycle arrest
- repair DNA damage
- induce apoptosis
How are p53 levels kept low? (3)
- after synthesis, p53 is bound to Mdm2
- Mdm2 serves as a marker by tagging p53 with ubiquitin
- to mark it for degradation by proteasome
What degrades RTKs?
Lysosomes
What degrades p53?
Proteasomes
How is the degradation of p53 prevented when needed? (3)
- when cells incur DNA damage, a signalling cascade is initiated which leads to the phosphorylation of p53
- prevents binding of Mdm2
- hence blocking its degradation
Intrinsic Induction of Apoptosis (4)
1) Apoptotic stimulus causes activation of p53, which induces expression of p53 up-regulated modulator of apoptosis (PUMA)
2) PUMA activates Bax and Bak
3) Bax and Bak form pores in the mitochondrial membrane causing the release of cytochrome C
4) This triggers activation of capsases and apoptosis
What blocks the action of Bax and Bak?
Bcl2 and BclXl
Capsase activation (2)
- cleavage of actin and breakdown of the cytoskeleton
- cleavage of nuclear lamina, nuclear shrinkage and DNA fragmentation
What does p38 act as?
Tumour suppressor
How is p38 be activated? (2)
- cellular stress
- DNA damage
What can p38 mediate?
Apoptosis
How does the p38 MAPK pathway lead to apoptosis? (5)
1) cellular stress activates TAK
2) TAK activates MKK 3/6
3) MKK 3/6 activates p38
4) Phosphorylation of p38 activates p53
5) Phosphorylation of p53 leads to apoptosis
Cisplastin and its function (2)
- chemotherapy drug
- activates p38 MAPK which activates p53 for apoptosis
How does the JNK MAPK pathway lead to immune response? (6)
1) Immune stimulation activates cytokines TNF-alpha
2) TNF-alpha binds to TNFR, leading to receptor activation
3) MAP3K is activated, which phosphorylates and activates MKK 4/7
4) this phosphorylates and activates JNK
5) JNK activates transcription factors
6) Immune response is induce (T-cell activation, Apoptosis, Inflammation)
