week 10b Flashcards
What are the 2 things the cell cycle consists of?
– Interphase: G1, S and G2 phases
– Mitotic phase (M): Mitosis and Cytokinesis
slides 1-7
week10
What is cancer?
Cancer is uncontrolled cell growth:
an abnormal growth of cells which tend to
proliferate in an uncontrolled way and, in some
cases, to metastasize (spread).
The frequency of cell division varies with cell type
– Skin cells divide frequently throughout life
– Liver cells maintain ability to divide in response to a
certain need
– Nerve cells do not divide in a mature human
how is The cell cycle is regulated?
• The cell cycle is regulated by a molecular control system
– Cytoplasmic molecules regulate progress through the cell
cycle
what are the The control points called in cell cycle? (stop and go ahead signals)
what do they do and how?
• The control points are known as Checkpoints
– They control the transition from one phase of the cell cycle
to the next one
– They ensure that certain processes have been completed
(e.g. completion of DNA replication, presence of growth
factors) before another phase starts
3 important Checkpoints:
– G1 Checkpoint
– G2 Checkpoint
– M Checkpoint
G1 Checkpoint (also called G1/S checkpoint or Restriction point R):
where?
Function?
– At the end of G1 phase (e.g. checks for the presence of growth
factors)
– Controls the transition from the G1 phase to the S phase (DNA
replication)
G2 Checkpoint:
– Controls the transition from the G2 phase to the Μ phase
mitosis
M (Metaphase) Checkpoint:
example?
– Controls the transition through mitosis stages
e.g. correct chromosome alignment in the mitotic spindle during metaphase
What does G1 checkpoint check for?
-Check extracellular environment? Growth
factors?
-Check DNA damage?
-Check if the cell size is
ok (is the cell large
enough to divide)?
what does G2 checkpoint check for?
-Check DNA damage?
-Check DNA replication
completion?
What does M checkpoint check for?
Are all the chromosomes
correctly aligned in the
mitotic spindle?
checkpoints summary of checks for
- G1: checks for cell size, nutrients, growth factors, DNA damage.
- G2: checks for DNA damage, DNA replication completion
- M: checks for chromosome alignment at mitotic spindle
What happens if any damage is detected?
- If any kind of damage (e.g. DNA damage) is
detected at the checkpoints G1 and G2
this will lead to cell cycle arrest (also
known as cell cycle
block) - This gives the opportunity to the cell to try
to repair this damage - If this is not possible, this will lead to
apoptosis (programmed cell death)
what is the most important checkpoint for many cells?
what happens to cell after?
G1
• After G1 checkpoint the cells commits to the cell cycle in the absence of growth factors (mitogenic stimulation no longer needed)
What proteins maintain the cell cycle control?
– Cyclin (cyc): the regulatory subunit
– Cyclin depended kinase (cdk): the catalytic subunit
what are Kinases enzymes?
• Kinases are enzymes that inactivate/activate other proteins
by phosphorylation
How does Cdks become activated? (Cyclin depended Kinase)
• Cdks are present at a constant concentration in the cell and
are inactive most of the time and become
—-activated by
binding to a particular cyclin
what happens to the concentration of cyclins in the cell?
The concentration of cyclins fluctuates in the cell
Function of The active form of cdks (cyc-cdk)?
exmaple?
• The active form of cdks (cyc-cdk) can phosphorylate various
proteins and can lead to protein activation or inactivation
– e.g. phosphorylation of G1/S transcription factors necessary
for DNA replication
Binding of cdks
to different ————–»»
cyclins
Phosphorylation
of different
substrates
Proteasome defintion?
Whats its role in the cell cycle(cdks and cyclins)
• The activity of cdks is regulated by degradation of cyclins by the
proteasome
– Proteasome: giant protein complexes that bind to protein molecules (short lived proteins such as cyclins and misfolded proteins) and degrade them (proteolysis)
Why is tight regulation of the cdks important?
• Tight regulation of cdks is very important
– Loss of cell cycle control can lead to unregulated cell
proliferation => carcinogenesis
What causes carcinogenesis
Loss of cell cycle control can lead to unregulated cell proliferation
What is MPF(Mitosis Promoting Factor/ also called Maturation Promoting Factor)
The signal that sends cells into mitosis
MPF
fact?
Consists of what?
Induces Progression of what?
- MPF was the first Cdk to be discovered
- MPF consists of a mitotic cyclin (cyclin A or cyclin B) and cdk-1
• MPF induces the progression from G2 to M phase by:
– phosphorylation and inactivation of E3 ubiquitin
ligase/Anaphase promoting complex (APC)
– phosphorylation of proteins of the nuclear lamina→
fragmentation of the nuclear envelope
MPF consists of what (asked again btw)?
consists of a mitotic cyclin (cyclin A or cyclin B) and cdk-1
APC (Anaphase Promoting Complex)
Function
inactivates mitotic
cyclins (cyc-A/cyc-B) and hence MPF during interphase
-Proteolysis of mitotic cyclins at the end of mitosis =>
reduction of ΜPF activity
ΜPF role: cell cycle regulation in Mitosis
- Chromosomal condensation
- Nuclear envelope degradation
- Mitotic spindle formation
- Chromosome migration to opposite poles
- Organelle reformation
- Cytokinesis
Cell cycle regulation during interphase
Steps(4)?
1 .Growth factor (mitogen) signalling
2 .Expression of early response genes
3 .G1 cyclin-dependent kinase (CDK)
activity
4 T.ranscription of genes encoding proteins
required for DNA synthesis
Cell cycle regulation during interphase
step 1?
Mitogens (growth factors)
Cell cycle regulation during interphase
step 2?
• 2. Expression of early response genes:
– G1 cyclins and cdks: cyc-D, cyc-E and cdks 2,4,6
– Transcription factors: E2F
• responsible for transcription of genes required for DNA replication (S phase genes: e.g. DNA polymerase)
Cell cycle regulation during interphase
step 3?
- Activation of G1 cyclin-cdk activity
Cell cycle regulation during interphase
step 4?
- Transcription of genes for DNA synthesis
• If the mitogen is removed:
– → reduction in the cyclin-cdk levels
– → the cell does not pass through the restriction point R
– → the cell does not replicate
(Mitotic) cyclins-cdks
cyc-A and cyc-B/ cdk-1 (MPF)
Which molecules make up the cell cycle
control system?
Any other key players?
- Cyclins/ Cdks
- Tumor Suppressor Genes
The cell cycle is tightly controlled by…………..
Tumour Suppressor
Genes
Function of the protein products of tumour suppressor genes
inhibit
cell division, thereby preventing the uncontrolled growth that contributes to cancer
Two very important tumour suppressor genes
-“RB1”
-“TP53”
which produce proteins Rb and p53 respectively
Retinoblastoma protein (Rb)
Funtions/steps (2)?
– Tumour suppressor gene →codes for tumour suppressor
protein→inhibits cell cycle progression
– Sequesters E2F → Inhibits E2F activation (during G1)
Regulation of Rb
Check slide44week10
– G1 phase: Rb dephosphorylation by PP-1 (protein phosphatase1)
– At the end of G1 phase cyc-cdks phosphorylate Rb
– Phosphorylated Rb cannot sequester E2F
– Ε2F is released (activated) => cell enters the S phase
What is Retinoblastoma?
How is it caused?
-a malignant tumour of the
eye(s) that originates from the retina
One (unilateral) or both (bilateral) eyes may be
affected and typically occurs in children less than
five years old.
-Worldwide, about 6000 children develop
Retinoblastoma each year. It affects 1:15000
births.
- There are two forms of the disease; a familial
(heritable) and sporadic (non-heritable) form.
-This disease is caused by a mutation in the
tumour suppressor gene RB1 which encodes for
the Rb protein
Negative regulators (inhinitors) of the cell cycle?
Cdk inhibitors (CKIs): inhibit the activity of the cyclin-cdk complexes
2 major types of Cdk inhibitors (CKIs):
– INK4 family:
• inhibit the activity of G1 cyclins cdks
– Cip/Kip family:
• inhibit the activity of all other cyc-cdk complexes
• their expression is strongly stimulated by DNA damage =>
p53 activation
WHat is p53:
diagram49
major tumour suppressor protein activated by
DNA damage
=> causes cell cycle arrest at G1 phase
Mutations in p53
More than 50% of all human tumours have a mutation in the p53 gene
Internal and External Signals at the Checkpoints
Both internal and external signals control the cell cycle
progression at checkpoints
Internal signals: at the checkpoints
e.g. cell size, incorrect alignment or separation
of sister chromatids (at M phase checkpoint)
External signals: at the checkpoints
e.g. environmental conditions, presence of
growth factors
Growth factors and examples
Growth factors stimulate other cells to divide
– Example: PDGF (platelet-derived growth factor) stimulates fibroblast
growth in a wound or a culture
(externsl signals)Density-dependent inhibition
crowded cells stop dividing
(Extern signals)Anchorage dependence:
most animal cells must be attached to a substratum (support) in order to divide
Normal mammalian
cells
The availability of nutrients, growth factors, and a substratum for attachment limits cell density to a single layer
Do Cancer cells exhibit Density-dependent inhibition or anchorage dependence
NO
What is The process by which a normal cell becomes a cancer cell
transformation
Normal cells vs Cancer cells
Normal cells:
• Density dependent
inhibition
• Anchorage dependence
Cancer cells: • No Density dependent inhibition • No anchorage dependence
Cancer cells and response to body control mechanisms
– make their own growth factors
– have a signaling pathway always ‘ON’
– abnormal cell cycle control
– Form tumors
Benign tumors
Malignant tumors
• Benign tumors: not invasive, contained at a particular
site
• Malignant tumors: invasive, can spread to other organs
Cancer cells characteristics
diagram58
1 .sustaining proliferative signaling
- Evading growth suppressors
- Activating invasion and metastasis
- Enabling replicative immortality
- Inducing angiogenesis
- Resisting cell death
Summary: Cell cycle control by cyc-cdks
G1 phase: ((Cyclins))cyc-D and cyc-E//// ((Cdks)) cdk-2,4,6
S phase : ((Cyclins)) cyc-A //// ((Cdks)) cdk-2
G2/M phase : ((Cyclins)) cyc-A and cyc-B//// ((Cdks)) cdk-1
Note: cyc-A/cdk-1 and cyc-B/cdk-1 = MPF
