Tumor Suppressor/Apoptosis Regulators/Other

Question 1

What are the 2 classic examples of tumor suppressor genes?

Answer 1

p53

Rb

Question 2

In response to REVERSIBLE DNA damage, what does p53 upregulate?

Answer 2

DNA REPAIR ENZYMES -> Slows down progression of G1 to S phase

Question 3

In response to IRREVERSIBLE DNA DAMAGE and impossible DNA repair, what enzyme does p53 upregulate?

Answer 3

Directs for APOPTOSIS
p53 upregulates BAX -> BAX disrupts BCL2 (stabilizes mitochondrial membrane so that cytochrome c doesn’t leak out) -> CYTOCHROME C leaks out -> Activates CASPASES -> Cellular apoptosis

Question 4

What is BCL-2?

Answer 4

BCL-2 = ANTI-APOPTOTIC GENE that stabilizes mitochondrial membrane
Prevents cytochrome c from leaking out of mitochondria and activating apoptosis

Question 5

What transition of the cell cycle does p53 regulate?

Answer 5

G1 to S phase

Question 6

What type of mutation must occur with p53/Rb to result in tumor formation?

Answer 6

LOF:

KNUDSON 2-hit hypothesis: Both copies of p53/Rb must be lost to tumor formation

Question 7

How are p53 mutations generally inherited? What is an exception of this?

Answer 7

USUALLY both copies of p53 are eliminated SOMATICALLY

**Exception = Li-FRAUMENI SYNDROME (SBLA: Sarcoma, breast, leukemia, adrenal gland syndrome) = autosomal dominant GERMLINE mutation of ONE copy of p53, second hit = SOMATIC

Question 8

What is the normal function of Rb? What transition of the cell cycle does it regulate?

Answer 8

Regulation of G1-> S phase

Rb sequesters E2F (a Tx factor necessary for transition to S phase) -> Prevents progression through cell cycle + uncontrolled cell growth

Question 9

How is Rb normally regulated?

Answer 9

Rb normally regulated by CYCLIN D/CDK4 - cyclin-dependent kinase phosphorylates Rb -> Frees E2F -> Can progress to S phase of cell cycle

Question 10

How does Rb mutation result in UNCONTROLLED CELL GROWTH and PROGRESSION THROUGH CELL CYCLE?

Answer 10

Rb mutation - Does not bind to E2F -> Constitutively FREE E2F -> Free activation of S phase -> Uncontrolled cell growth

Question 11

If pt has both copies of Rb knocked out SOMATICALLY, what is the pt likely to develop?

Answer 11

SPORADIC UNILATERAL RETINOBLASTOMA

Question 12

If pt has first copy of Rb knocked out by GERMLINE mutation, and the second one SPORADICALLY, what are two carcinomas that the pt is likely to develop?

Answer 12

FAMIAL BILATERAL RETINOBLASTOMA

OSTEOSARCOMA

Question 13

What is an important apoptosis regulator (anti-apoptotic gene) that stabilizes the mitochondrial membrane and prevents leakage of cytochrome c?

Answer 13

BCL-2

Question 14

Which tumor results from an over-expression of BCL-2? What is the underlying mutation?

Answer 14

FOLLICULAR LYMPHOMA

t(14;18) chromosomal translocation - Chrom 14: IgH locus, Chrom 18: BCL-2

Question 15

What process does BCL-2 OVEREXPRESSION in a FOLLICULAR LYMPHOMA prevent?

Answer 15

Prevents apoptosis (SOMATIC HYPERMUTATION) in LYMPH NODE GERMINAL CENTER

Question 16

What is the normal function of telomeres with regards to cellular aging?

Answer 16

Normally, telomeres SHORTEN with serial cellular divisions -> Results in SENESCENCE (Cell death with no further ability to divide)

Question 17

How do cancers inhibit senescence with regards to telomere shortening?

Answer 17

Cancers have UPREGULATED TELOMERASE
(Reverse transcriptase enzyme that carries its own RNA molecule as a template for elongating telomeres) -> Preserves telomeres -> Prohibit SENESCENCE (=telomere shortening)

Question 18

What are two angiogenic factors that are commonly produced by tumor cells?

Answer 18

FGF

VEG-F

Question 19

What is one way that tumor cells can PERVADE IMMUNE SURVEILLANCE? Think of how tumor cells can often be detected.

Answer 19

DOWNREGULATION OF MHC CLASS I

Pts with IMMUNODEFICIENCY have increased risk of cancer

Question 20

SUMMARY SLIDE OF ALL APOPTOSIS REGULATORS/ TUMOR SUPPRESSORS/ OTHER (3):

Answer 20

• TUMOR SUPPRESSOR: 2somatic OR 1germline/1somatic p53 loss [LI FRAUMENI, SBLA]
• TUMOR SUPPRESSOR: 2somatic [sporadic, unilateral] OR 1 germline/1somatic Rb loss [familial, bilateral]
• APOPTOSIS REGULATOR: BCL-2 overexpression = FOLLICULAR LYMPHOMA
• OTHER: INCREASED TELOMERASE
• OTHER: INCREASED FGF/VEGF
• OTHER: DECREASED MHC CLASS I EXPRESSION