Cancer Intro

Question 1

Cancer

Answer 1

A disease of uncontrolled cell division

Question 2

Development and progression of Cancer is usually linked to…

Answer 2

Changes in the activities of cell cycle regulators

–> A loss of cell cycle control

Question 3

Main molecular causes of Cancer (4):

Answer 3

1) Growth Factor Abnormalities
2) Signaling Machinery Defects
3) Improper Replication
4) Failure of Apoptosis

Question 4

Growth Factor Abnormalities (Cancer) (2)

Answer 4

1) Make their own growth factors
2) Growth factor pathways are always ON

Question 5

Genes for growth factors in normal cells are usually _______ and only _________ ____ when needed

–> How is this changed in cancer cells?

Answer 5

1) OFF
2) TURNED ON
–>These genes are usually selectively activated

–> In Cancer cells, mutations in these genes cause them to ALWAYS be ON = production of growth factors even when not needed
–> Don’t need the appropriate signal to activate the production of growth facotrs

Cancer cells don’t need a signal to activate the production of growth factors

Question 6

Cancer cells may have abnormal signaling pathways that are…

Answer 6

ALWAYS ON (Constitutively active)

OR

that fail to convey growth factor signals (specifically STOP signals from a lack of the growth factor)

Question 7

Some Cancer cells have been observed “tricking”…

Answer 7

neighboring cells into producing their own growth factors

Question 8

Signaling Machinery Defects in Cancer cells

Answer 8

Have defects in cdks or other singaling machinery that ensures DNA replication and mitosis occur only under FAVORABLE conditions

–> Usually defects in machinery that STOPS cell division

Question 9

What is the result of signaling machinery defects in Cancer cells?

Answer 9

Cells with continue to divide even under UNFAVORABLE conditions

–> They can’t stop themselves

Question 10

Improper replication/division in Cancer Cells

Answer 10

IF and when Cancer cells do STOP dividing, they usually do so at random points (not at the regular checkpoints)

Question 11

What is the result of improper replication/division in Cancer Cells?

Answer 11

Creates abnormal cells that have stopped dividing at random points in the cell cycle

–> Usually produces cells with severe deformities such as wrong # chromosomes

–> These cells will continue on to divide, proliferating the damage and abnormalities
Proliferation of damaged cells

Question 12

Failure of apoptosis in Cancer Cells

Answer 12

Cancer cells typically fail to undergo apoptosis even under conditions in which normal cells would (ie. DNA damage)

Question 13

Apoptosis in Normal vs Cancer Cells

Answer 13

Normal Cells –>
Unfixable DNA Damage = APOPTOSIS

Cancer Cells –>
Unfixable DNA Damage = Cells continue dividing

Question 14

Main families of genes causing Cancer:

Answer 14

1) Oncogenes
2) Tumor Suppressors

Question 15

Oncogenes

Answer 15

Genes that normally promote cell division (when not mutated)

Question 16

What do oncogenes encode for?

Answer 16

1) Growth Factors
2) Growth Factor Receptors
3) Regulatory proteins of signaling pathways involved in cell division

Question 17

Oncogene vs Proto-Oncogene

Answer 17

Oncogene = The over-active (Cancer promoting) form of these genes

Proto-Oncogene = The not-yet-mutated (normal) form

Question 18

First identified human oncogene

Answer 18

RAS

Question 19

RAS (gene)

Answer 19

A family of genes that encode for the G-Protein (GTPase), Ras

Question 20

Ras (protein)

Answer 20

A G-Protein (GTPase)

–> Relays a signal from a growth factor receptor (TK) to a cascade of protein kinases

Question 21

GTPase

Answer 21

A G-Protein that is active when bound to GTP

Question 22

Ras signaling pathway causes…

Answer 22

Upregulation of Cyclin D levels

Question 23

Cyclin D

Answer 23

Required for transition from G1 to S phase (G1 checkpoint)

Question 24

Ras Pathway Steps

Answer 24

1) Growth factor binds to a Tyrosine Kinase Receptor

2) The TK receptor auto-phosphorylates
–> 2.1) Ras-GDP (inactive form) gets activated to Ras-GTP

3) Active Ras initiates the phosphorylation cascade involving various protein kinases

4) Cascade leads into the nucleus where a transcription factor is activated

5) Leads to transcription of the gene encoding for Cyclin D production

6) Cyclin D is produced

7) Cell cycle is stimulated (pushed through G1 checkpoint)

Question 25

In Cancer, Ras protein is…

Answer 25

HYPERACTIVE

–> It’s always “ON” = Always in the GTP bound (active) form

Question 26

Due to Ras being hyperactive…

Answer 26

There is continuous transcription of the Cyclin D gene === overproduction of Cyclin D

*** Means Ras is ON without a growth factor “turning it on”
–> Doesn’t need the growth factor signal to induce Cyclin D production, it simply does it all the time

Question 27

Normal vs Cancerous Ras Pathway

Answer 27

NORMAL
Ras-GDP <—-> Ras-GTP = Controlled Proliferation

CANCER
Ras GDP ——> Ras-GTP = Uncontrolled Proliferation

Question 28

Problems with inhibiting Ras as a treatment?

Answer 28

Ras is an essential component of the normal cell response to growth factors

–> Inhibiting Ras would also affect healthy/normal cell division

Question 29

What percent of Cancers have a Ras mutation?

Answer 29

20% of all human cancers

Question 30

Tumor Suppressors

Answer 30

Genes that normal SUPPRESS cell division (when not mutated)

Question 31

What do tumor suppressors encode for?

Answer 31

Encode proteins that HALT cell cycle progression

Question 32

p53 (protein)

Answer 32

The best characterized tumor suppressor protein

–> A transcription factor that binds and activates specific genes that encode for proteins that arrest the cell cycle, promote DNA repair, and promote apoptosis

Question 33

What does p53 do?

Answer 33

Acts at the G1 checkpoint to HALT the cell cycle in response to DNA damage

Question 34

In response to DNA damage, p53…

Answer 34

1) Stops cell cycle progression
2) Initiates DNA repair pathway
3) Promotes apoptosis (if needed)

Question 35

What is p53 known as? Why?

Answer 35

“The Guardian of the Genome”

–> Prevents the proliferation of damaged cells, specifically those with abnormal genetic content

Question 36

p53 Pathway

Answer 36

1) DNA Damage in cell –> p53 is bound to DNA

2) p53 activates 2 genes:
2.1) Activates gene that transcribes p21
2.2) Activates gene that transcribes DNA repair enzymes
3) The genes transcribe their respective encoded proteins

4) p21 = cyclin inhibitor = inhibitor of the active cdk-cyclin complex

5) G1 checkpoint arrests (prevents DNA replication)

6) DNA repair enzyme attempts to repair DNA
6.1) If DNA is repaired = Cell cycle continues
6.2) If DNA is NOT repaired = apoptosis

Question 37

p21

Answer 37

Cyclin Inhibitor –> Gets created (transcribed) thanks to p53 activating the gene that encodes for p21

Question 38

p53 in Cancers

Answer 38

Usually non-functional, missing, or under-active

== No arresting of cell cycle and/or repair of DNA

Question 39

Main mutation affecting p53

Answer 39

Causes the p53 protein unable to bind to DNA

Question 40

p53 and Ras as the most frequently mutated gene in human cancers:

Answer 40

~1/2 of all tumors contain a mutation in p53 or Ras