Life and Death of the cell

Question 1

What is endocrine signaling?

Answer 1

hormone secretion into blood by endocrine gland to influence distant target cells

Question 2

What is autocrine signaling?

Answer 2

targets a site on the same cell

Question 3

what is paracrine signaling?

Answer 3

secretory cell releases signals that impact an adjacent target cell

Question 4

what is the difference between external and internal signals for cell proliferation?

Answer 4

external signals - bind to receptors on the cell surface

intracellular signalling triggere activation of proliferative pathways inside of the cell

Question 5

what are the three types of extracellular signlas regulating cell prolifeartion/ cell death?

Answer 5

1. mitogens- stimulate cell division by relieving intracellular negative controls that block cell cycle progress
2. growth factors- stimulate cell growth (increased cell mass) by promoting synthesis of proteins and by inhibiting their degradation
3. survival factors- promote cell survival by suppressing apoptosis (programmed cell death)

Question 6

what type of molecules are growth factors usually?

Answer 6

usually a protein or steroid hormone that binds to specific receptors on the cell surface and transduce signal into cell

Question 7

what are cyclin-cyclin depdendent kinase complexes?

Answer 7

CDK complexes regulate transition through the cell cycle

1. G1 cyclins help promote passage through the restriction point in late G1
2. G1/S-cyclins bind Cdks at the end of G1 and commit the cell to DNA replicaiton
3. S-cyclins bind Cdks during S phase and are required for the initiation of DNA replicaiton
4. M-cyclins promote the events of mitosis

Question 8

what is the cyclin dependent kinase complex composed of?

Answer 8

cyclins + cyclin dependent kinases = cyclin dependent kinase complex

Question 9

What are cyclins?

Answer 9

they are regulatory subunits- increase and decrease during cell cycle - act as substrate for CDK enzyme switching on kinase activity degraded at certain points in cell cycle

Question 10

do CDKs or cyclins fluctuate during the cell cycle?

Answer 10

levels of CDK are steady

but levels of cyclin proteins fluctuate during the cell cycle

Question 11

what activates Cyclin dependent kinases?

Answer 11

Cyclin binding - causes partial activation of CDK, then phosphorylation by ‘CDKactivating kinase’ activates the enzyme fully

Question 12

describe the loss of cell cycle regulation in mantle cell lymphoma

Answer 12

expression of cyclin D1 is placed under control of the IgH promoter

as a result of chromosomal translocation, the upregulation of cyclin D 1 is induced

Cyclin D1 is bound to CDK4 - activates the transcription factor E2F -releasing it from negative regulation by the tumor suppressor Rb -

E2F drives the cell cycle through the G1-S phase of the cell cycle

Question 13

what does the addition of growth factor to G0 arrested cells do?

Answer 13

it induces transcription of many genes - some early response genes are transcription factors that activate transcription of late response genes

late response genes include mid and late G1 cyclins and Cdks- activate genes invovled with DNA synthesis

Question 14

What is p53?

Answer 14

the ‘guardian of the genome ‘

• transcription factor
• activated by DNA damage
• stops cell replicating
• p53 mutations are prevalent in many cancers

Question 15

describe how p53 works?

Answer 15

it is a tumor supressor

• induces p21, which inhibits kinase activity of cyclin -cdk complex, Rb is not phosphorylated and remains boudn to E2F - S phase genes NOT turned on
• if DNA damage is repaired, p53 levels drop, p21 decreases so the cyclincdk can phosphorylate Rb to release E2F- S phase genes turned on and cell proliferation proceeds
• If DNA damage not repaired - p53 remains high and cel undergoes apoptosis

Question 17

what’s the difference between apoptosis and necrosis?

Answer 17

apoptosis = cell death which is a programmed sequence of events that leads to elimination of cells without releasing harmful substances into the surrounding area

necrosis = occurs when a cell is damaged by an external force such as poison, injury, lack of blood supply etc

Question 18

What role do extrinsic signals have in the regulation of apoptosis?

Answer 18

Extrinsic signals - initiated from neighboring cells - most cells require signals to stay alive “trophic factors” the absence of trophic factors causes cells to activate apoptosis

in other instances, cells recieve signals to commit suicide from other cells, particularly important in developmental process

Question 19

what role to intrinsic signals play in apoptosis?

Answer 19

intrinsic signals - cell senses damage and initiates its own death - if DNA damage exceeds the repair capabilities of the cell integrity of DNA is impaired

Question 20

what is the difference between the extrinsic and intrinsic pathway of cell death?

Answer 20

Extrinsic

• initiated by formation of a death -inducing cell surface receptor signalling complex
• leads to activation of initator caspase 8

Intrinsic

• mediated by changes in mitochondrial function
• regulated by anti-apoptotic Bcl2 family members
• associated with activation of initator caspase 9

Question 21

what activates the “death receptor” of the extrensic apoptotic pathway?

Answer 21

• ligand binds
• trimerisation of receptor
• activation of initiator pro-caspase 8
• activates other caspases ultimately leading to apoptosis

Question 22

what role does p53 play in the intrinsic apoptotic pathway?

Answer 22

• cytoplasmic P53 antagonises anti-apoptotic effect of Bcl2- which results in the mitochondrial outer-membrane permeabilization and release of cytochrome C into cytosol
• Cytochrome C binds to Apaf1 - apoptotic protease activating factor
• cytochrome C-Apaf1 complex binds to initiator caspase 9
• the pro-apoptotic proteins activate caspase 9
• caspases induce DNA fragmentation

Question 23

actions of caspases results in???

Answer 23

• DNA fragmentation by endonuclease
• loss of cell shape and organelle breakdown
• cell fragmentation into apoptotic bodies
• apoptotic bodies phagocytosed by macrophages

Question 24

What role does overexpression of BCL2 have in cancer?

Answer 24

it is an anti-apoptotic protein - so overexpression of BCL2 is found in a number of forms of leukemia

Question 25

What role do ‘decoy receptors’ play in cancer?

Answer 25

Decoy receptors - bind death signal ligands but do not transduce signal -

these are overexpressed in many cancers