week 10b

Question 1

What are the 2 things the cell cycle consists of?

Answer 1

– Interphase: G1, S and G2 phases

– Mitotic phase (M): Mitosis and Cytokinesis

Question 2

slides 1-7

Answer 2

week10

Question 3

What is cancer?

Answer 3

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).

Question 4

The frequency of cell division varies with cell type

Answer 4

– 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

Question 5

how is The cell cycle is regulated?

Answer 5

• The cell cycle is regulated by a molecular control system
– Cytoplasmic molecules regulate progress through the cell
cycle

Question 6

what are the The control points called in cell cycle? (stop and go ahead signals)
what do they do and how?

Answer 6

• 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

Question 7

3 important Checkpoints:

Answer 7

– G1 Checkpoint
– G2 Checkpoint
– M Checkpoint

Question 8

G1 Checkpoint (also called G1/S checkpoint or Restriction point
R):

where?
Function?

Answer 8

– 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)

Question 9

G2 Checkpoint:

Answer 9

– Controls the transition from the G2 phase to the Μ phase

mitosis

Question 10

M (Metaphase) Checkpoint:

example?

Answer 10

– Controls the transition through mitosis stages

e.g. correct chromosome alignment in the mitotic spindle during metaphase

Question 11

What does G1 checkpoint check for?

Answer 11

-Check extracellular environment? Growth
factors?

-Check DNA damage?

-Check if the cell size is
ok (is the cell large
enough to divide)?

Question 12

what does G2 checkpoint check for?

Answer 12

-Check DNA damage?

-Check DNA replication
completion?

Question 13

What does M checkpoint check for?

Answer 13

Are all the chromosomes
correctly aligned in the
mitotic spindle?

Question 14

checkpoints summary of checks for

Answer 14

• 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

Question 15

What happens if any damage is detected?

Answer 15

1. 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)
2. This gives the opportunity to the cell to try
   to repair this damage
3. If this is not possible, this will lead to
   apoptosis (programmed cell death)

Question 16

what is the most important checkpoint for many cells?

what happens to cell after?

Answer 16

G1

• After G1 checkpoint the cells
commits to the cell cycle in the
absence of growth factors
(mitogenic stimulation no longer
needed)

Question 17

What proteins maintain the cell cycle control?

Answer 17

– Cyclin (cyc): the regulatory subunit

– Cyclin depended kinase (cdk): the catalytic subunit

Question 18

what are Kinases enzymes?

Answer 18

• Kinases are enzymes that inactivate/activate other proteins
by phosphorylation

Question 19

How does Cdks become activated? (Cyclin depended Kinase)

Answer 19

• 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

Question 20

what happens to the concentration of cyclins in the cell?

Answer 20

The concentration of cyclins fluctuates in the cell

Question 21

Function of The active form of cdks (cyc-cdk)?

exmaple?

Answer 21

• 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

Question 22

Binding of cdks
to different ————–»»
cyclins

Answer 22

Phosphorylation
of different
substrates

Question 23

Proteasome defintion?

Whats its role in the cell cycle(cdks and cyclins)

Answer 23

• 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)

Question 24

Why is tight regulation of the cdks important?

Answer 24

• Tight regulation of cdks is very important
– Loss of cell cycle control can lead to unregulated cell
proliferation => carcinogenesis

Question 25

What causes carcinogenesis

Answer 25

Loss of cell cycle control can lead to unregulated cell proliferation

Question 26

What is MPF(Mitosis Promoting Factor/ also called Maturation Promoting Factor)

Answer 26

The signal that sends cells into mitosis

Question 27

MPF fact? Consists of what? Induces Progression of what?

Answer 27

* 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

Question 28

MPF consists of what (asked again btw)?

Answer 28

consists of a mitotic cyclin (cyclin A or cyclin B) and cdk-1

Question 29

APC (Anaphase Promoting Complex) Function

Answer 29

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

Question 30

ΜPF role: cell cycle regulation in Mitosis

Answer 30

* Chromosomal condensation * Nuclear envelope degradation * Mitotic spindle formation * Chromosome migration to opposite poles * Organelle reformation * Cytokinesis

Question 31

Cell cycle regulation during interphase Steps(4)?

Answer 31

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

Question 32

Cell cycle regulation during interphase | step 1?

Answer 32

Mitogens (growth factors)

Question 33

Cell cycle regulation during interphase | step 2?

Answer 33

• 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)

Question 34

Cell cycle regulation during interphase | step 3?

Answer 34

3. Activation of G1 cyclin-cdk activity

Question 35

Cell cycle regulation during interphase | step 4?

Answer 35

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

Question 36

(Mitotic) cyclins-cdks

Answer 36

cyc-A and cyc-B/ cdk-1 (MPF)

Question 37

Which molecules make up the cell cycle control system? Any other key players?

Answer 37

- Cyclins/ Cdks | - Tumor Suppressor Genes

Question 38

The cell cycle is tightly controlled by..............

Answer 38

Tumour Suppressor | Genes

Question 39

Function of the protein products of tumour suppressor genes

Answer 39

inhibit | cell division, thereby preventing the uncontrolled growth that contributes to cancer

Question 40

Two very important tumour suppressor genes

Answer 40

-"RB1" -"TP53" which produce proteins Rb and p53 respectively

Question 41

Retinoblastoma protein (Rb) Funtions/steps (2)?

Answer 41

– Tumour suppressor gene →codes for tumour suppressor protein→inhibits cell cycle progression – Sequesters E2F → Inhibits E2F activation (during G1)

Question 42

Regulation of Rb Check slide44week10

Answer 42

– 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

Question 43

What is Retinoblastoma? How is it caused?

Answer 43

-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

Question 44

Negative regulators (inhinitors) of the cell cycle?

Answer 44

``` Cdk inhibitors (CKIs): inhibit the activity of the cyclin-cdk complexes ```

Question 45

2 major types of Cdk inhibitors (CKIs):

Answer 45

– 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

Question 46

WHat is p53: diagram49

Answer 46

major tumour suppressor protein activated by DNA damage => causes cell cycle arrest at G1 phase

Question 47

Mutations in p53

Answer 47

More than 50% of all human tumours have a mutation in the p53 gene

Question 48

Internal and External Signals at the Checkpoints

Answer 48

Both internal and external signals control the cell cycle | progression at checkpoints

Question 49

Internal signals: at the checkpoints

Answer 49

e.g. cell size, incorrect alignment or separation | of sister chromatids (at M phase checkpoint)

Question 50

External signals: at the checkpoints

Answer 50

e.g. environmental conditions, presence of | growth factors

Question 51

Growth factors and examples

Answer 51

Growth factors stimulate other cells to divide – Example: PDGF (platelet-derived growth factor) stimulates fibroblast growth in a wound or a culture

Question 52

(externsl signals)Density-dependent inhibition

Answer 52

crowded cells stop dividing

Question 53

(Extern signals)Anchorage dependence:

Answer 53

``` most animal cells must be attached to a substratum (support) in order to divide ```

Question 54

Normal mammalian | cells

Answer 54

``` The availability of nutrients, growth factors, and a substratum for attachment limits cell density to a single layer ```

Question 55

Do Cancer cells exhibit Density-dependent inhibition or anchorage dependence

Answer 55

NO

Question 56

What is The process by which a normal cell becomes a cancer cell

Answer 56

transformation

Question 57

Normal cells vs Cancer cells

Answer 57

Normal cells: • Density dependent inhibition • Anchorage dependence ``` Cancer cells: • No Density dependent inhibition • No anchorage dependence ```

Question 58

Cancer cells and response to body control mechanisms

Answer 58

– make their own growth factors – have a signaling pathway always ‘ON’ – abnormal cell cycle control – Form tumors

Question 59

Benign tumors Malignant tumors

Answer 59

• Benign tumors: not invasive, contained at a particular site • Malignant tumors: invasive, can spread to other organs

Question 60

Cancer cells characteristics diagram58

Answer 60

1 .sustaining proliferative signaling 2. Evading growth suppressors 3. Activating invasion and metastasis 4. Enabling replicative immortality 5. Inducing angiogenesis 6. Resisting cell death

Question 61

Summary: Cell cycle control by cyc-cdks

Answer 61

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