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1

What are the 6 hallmarks of cancer?

1. Evade growth suppressors
2. Sustain proliferative signaling
3. Resist cell death
4. Induce angiogenesis
5. Enable replicative immortality
6. Activate invasion and metastasis

2

Cancer is a ___ disease.

Genetic

3

The incidence of cancer increases with age. What does this suggest?

Cancers do not arise from single mutations; they reflect accumulating mutations over time.

4

Cancers can arise from what two types of mutations?

1. Heritable germline mutation
2. Somatic de novo mutation

5

What are the two main types of cancer genes?

1. Oncogenes - drive cell cycle
2. Tumor suppressor genes - block cell cycle

6

What is the two-hit hypothesis?

This hypothesis states that many cancers require both copies of a gene to be mutated to lead to cancer. One germline copy of a damaged gene in every cell i not sufficient to develop cancer. Loss of the good copy of the gene could occur, producing cancer.

7

Tumor suppressors act ___ phenotypically; the germline mutation is inherited ___.

Recessive; autosomal dominant

8

What are the 6 oncogene pathways that drive the cell cycle and lead to the promotion of growth and malignancy of tumors?

1. Promote cell division
2. Inhibit apoptosis
3. Promote immortality
4. Promote angiogenesis
5. Promote metastasis
6. Promote genetic instability (via #2 and #3)

9

What are the 5 tumor suppressor gene pathways that normally prevent cancer by restricting growth?

1. Inhibit cell division
2. Promote apoptosis
3. Inhibit immortality
4. Inhibit angiogenesis
5. Inhibit metastasis

10

Provide an overview of apoptosis, beginning with the 3 stimulators of the central cell death signal and ending with phagocytosis.

TNFalpha and Fas death receptors, growth factor withdrawal, and DNA damage/activation of p53 can all activate the central cell death signal. This leads to protease activation of caspases. This leads to endonuclease activity, cell surface alterations, and cytoskeletal reorganization. This leads to phagocytosis. Bcl2 can block the cell death signal and CrmA and p35 can block protease activation of caspases.

11

What are the two apoptotic pathways?

1. Extrinsic - death receptor pathway
2. Intrinsic - mitochondrial-dependent pathway

12

Where is the cross-talk between the extrinsic and intrinsic pathways?

Caspase 8 can signal tBID.

13

What are caspases?

Cys/Asp proteases synthesized in the cell as inactive precursors

14

True or false - caspases can only be activated through the extrinsic pathway.

False - caspases can be activated by signals from both pathways.

15

How are caspases activated?

Cytosolic procaspases exist as inactive monomers (initiator caspase). The apoptotic signal triggers adaptor proteins, which trigger dimizeration, activation, and cleavage to form the active caspase. This activates (via cleavage) executioner caspases (inactivated as a dimer), which cleave at multiple substrates, leading to apoptosis.

16

What are the initiator caspases?

Caspases 8 and 9

17

What are the executioner caspases?

Caspases 3, 6, 7

18

What are the two domains of the initiator caspases (in their cytosolic procaspase form)?

1. Adaptor binding domain
2. Protease domain

19

Describe the process of DNA fragmentation during apoptosis.

1. CAD, an endonuclease, is inactivated by iCAD, an inhibitor.
2. An active executioner caspase cleaves iCAD, activating CAD.
3. CAD cleaves DNA between nucleosomes, leading to fragmentation.

20

The extrinsic pathway of apoptosis is activated through ___.

Fas death receptors

21

Describe the death receptor-mediated pathway.

1. Fas ligands (or other tumor necrosis factor ligands) bind to Fas death receptors.
2. Several ligand-bound receptor trimers cluster together.
3. The death domains on the receptor tails are activated.
4. The death domains interact with domains on the FADD (Fas-associated death domain).
5. FADD recruits initiator caspases (caspase 8) via a death effector domain on both FADD and the caspase, forming DISC (death inducing signaling complex)
6. Within DISC, 2 adjacent initiator caspases interact and cleave one another
7. Form activated protease dimer, which leaves itself
8. Stabilizes and releases active caspase dimer into the cytosol, leading to activation of the executioner caspases
9. Apoptosis

22

The intrinsic pathway of apoptosis depends on the ___.

Mitochondria

23

Describe the intrinsic pathway of apoptosis.

1. Apoptotic stimuli causes the mitochondria to release cytochrome c.
2. Cytochrome c activates Apaf1, which unfolds partly
3. CARD domain is exposed
4. 7 active Apaf1 proteins interact at CARDs to form the apoptosome
5. Recruit and activate caspase 9
6. Caspase 9 cleaves and activates executioner caspases
7. Apoptosis

24

Bcl-2 family members are related by regions of ___ and structural ___.

Sequence; homology

25

What are the three general types of Bcl-2 family members?

1. Anti-apoptotic Bcl2 family proteins (Bcl2, BclXL) - guardians
2. Pro-apoptotic effector Bcl2 family proteins (Bax, Bak) - effectors
3. Pro-apoptotic BH3-only proteins (Bad, Bim, Bid, Puma, Noxa) - initiators

26

Describe the differences in shared domains between the guardians, effectors, and initiators of the Bcl-2 family.

Guardians have BH4, BH3, BH1, BH2, TM. Effectors have all except BH4. Initiators only have BH3.

27

___ proteins regulate the intrinsic pathway of apoptosis. Describe how this occurs.

Bcl2 proteins; Inactive effector Bcl2 family proteins exist as monomers. An apoptotic stimulus leads to aggregation of effector Bcl2 family proteins on the outer mitochondrial membrane. This leads to the release of cytochrome c and other proteins.

28

In the absence of an apoptotic stimulus, what do anti-apoptotic Bcl2 family proteins do?

Bind to and inhibit the effector Bcl2 family proteins on the mitochondrial outer membrane.

29

In the presence of an apoptotic stimulus, what do BH3-only proteins do?

BH3-only proteins are activated and bind to the anti-apoptotic Bcl2 family proteins, inhibiting their inhibition. Note that some BH3-only proteins can stimulate mitochondrial protein release by directly binding to and activating the effector Bcl2 family proteins.

30

The activation of p53 triggers ___ via upregulation of ___ expression. Describe this process.

Apoptosis; BH3-only; DNA damage leads to kinase activation. p53 is phosphorylated, Mdm2 falls off, and p53 increases. This leads to transcription of many genes, including BH3-only genes (Puma and Noxa). BH3-only proteins bind to Bcl2, activating the intrinsic apoptotic pathway.