Biochem Exam 3: Molecular Biology Of Cancer

Front 1

What type of cancer will result from cells originating in (a) epithelial (b) mesenchymal (c) WBCs

Back 1

(a) carcinoma (b) sarcoma (c) leukemia/lymphoma

*carcinomas & sarcomas have solid tumors

Front 2

What are the differences btw familial vs. sporadic cancer?

Back 2

Familial -- Involves germline and somatic mutations; multiple tumors, early onset, bilateral.

Sporadic -- Two somatic mutations; 1 tumor, later onset, unilateral.

Front 3

What is the mechanism by which cigarette smoke causes DNA mutations?

Back 3

Polycyclic hydrocarbons (from smoke) converted to epoxides via aryl hydrocarbon hydroxylases (CYP) leading to DNA mutations (lung cancer).
(Note: enzyme is inducible and in pts w/hi-inducability allele will be more prone to CA)

Front 4

What class of proto-oncogenes and what CA is caused by the following oncogenes
(a) Abl
(b) Myc
(c) Telomerase

Back 4

(a)cytoplasmic tyrosine kinase, CML (chronic myelogenous leukemia) *cell signaling
(b) transcription factor, Burkitt lymphoma *gene transcription
(c) Telomerase, Many types of cancer * cell senescence

Front 5

What translocation has been assoc. with Burkitt lymphoma?

Back 5

MYC proto-oncogene from chromosome 8 to 14 resulting in expression by promoter region of IG heavy chain genes.
t(8;14)(q24;q32)
t(8;22)(q24;q11)
t(2;8)(p12;q24)
*characteristic B-cell tumors in Jaw- equatorial Africa

Front 6

What chromosomal translocation is associated with CML (chronic myelogenous leukemia)?

Back 6

ABL proto-oncogene translocates from 9 to 22 and is joined by BCR resulting in inc. tyrosine kinase activity creating excess myeloid precursors.
t(9;22)(q34;q11)
*altered 22 known as Philadelphia chromsome

Front 7

Describe the mechanism of the following viruses in CA (a) HPV (b) HTLV-1

Back 7

(a) Viral proteins inactivate tumor suppressors Rb and p53 (b) Tax protein of virus is a coactivator for proto-oncogenes resulting in T cell leukemia

Front 8

Describe the mechanism of the following viruses in CA : HIV

Back 8

Tat transcription factor of the virus activates synthesis of cytokines promoting T cell proliferation and causing non-Hodgkin lymphoma

Front 9

Describe the 3 main proteins involved in the regulation of the cell cycle.

Back 9

1. Cyclins:
regulate cell cycle (proto-oncogene)
Cyclins (inducible) must combine to cycline dependent kinases (constitutive) to become active.
2. Cyclin dependent kinases (CDKs):
(constitutive, proto-oncogenes)
3. Cyclin dependent kinase inhibitors (CKIs):
(inducible, tumor suppressors)
bind to active complex (cyclin + CDK) to make it inactive

Front 10

How do activated cyclin dependent kinases act on the cell?

Back 10

Phosphorylate retinoblastoma protein causing it to dissoc. from E2F transcription factor. Thus, E2F can cause cell cycle progression from G1 to S. Mutation of Rb leads to retinoblastoma.

Front 11

What is p53?

Back 11

It is a tumor suppresing transcription factor. p53 initiates transcription of repair enzymes and p21 (a CKI) leading to cell cycle arrest. Can also initiate apoptosis.

Front 12

What is the inheritance pattern and cause of Li-Fraumeni syndrome?

Back 12

Autosomal dominant. Caused by p53 mutations leading to many different cancers.

Front 13

What is neurofibromin (NF-1)?

Back 13

tumor suppressor that deactivates RAS by hydrolyzing GTP. (RAS is active in MAP kinase cascade).
Mutation in NF-1 can lead to neurofibromatosis.

Front 14

What are cadherins and catenins? Specifically what is beta catenin?

Back 14

Cadherins - mediators in cell to cell contact (tumor suppressor).
Catenins - bind actin to cadherins.
B catenin is also a transcription activator (proto-oncogene).

Front 15

How is beta catenin usually regulated? What CA is assoc. with this regulation pathway?

Back 15

Inactive by being bound to cadherins and APC (adenomatous polyposis coli). APC mutations/deficiencies lead to familial polyposis colon CA.

Front 16

What pathologies are assoc. with RecQ BLM helicases?

Back 16

Bloom's syndrome.
Werner syndrome (premature aging).
Rothmund-Thompson syndrome (skin abnormalities).

Front 17

What are caspases?

Back 17

Cysteine proteases secreted as proenzymes (inactive) and activated by proteolytic cleavage to induce apoptosis.
-pro-apoptotic molecules (tumor suppressors)

Front 18

What number caspases are initiators? Execution?

Back 18

8,9,10.
3,6,7.

Front 19

What cascade occurs after mitochondria perceives death signals?

Back 19

Release of cytochrome C (CYM C) from mitochondria. Binds to apoptotic protease activating factor 1 (Apaf1) and activates capase 9.

Front 20

Name 3 anti-apoptotic proteins and describe their function.

(Bcl-2 family)

Back 20

BCL-2, BCL-X, BCL-W. Can bind and inactivate Apaf 1 and antagonize the actions of proapoptotic factors (BH3-only).

Front 21

Name 3 proapoptotic channel forming proteins and describe their function.

(Bcl-2 family)

Back 21

BAX, BAK, BOK. Form channels in outer mitochondrial membrane -- releasing CYM C. Dependent on binding of BH3-only (pro-apoptopic) members.

Front 22

Name 3 pro-apoptotic BH-3 only proteins and describe their function.

(Bcl-2 family)

Back 22

BAD, BID, BIM. Regulate anti and channel-forming proapoptotic factors.

Front 23

What translocation is involved in follicular B cell lymphoma?

Back 23

BCL-2 translocation from 18 to 14 and places it under promoter control of IG heavy chain genes. Elevated BCL-2 proteins lead to dex. cell death and lymphoma.

Front 24

Benign vs malignant tumors

Back 24

benign tumors- a tissue w/ abnormally high cell number (neoplasm), do not have invasive properties, genetic/epigenetic transformation of normal cells

malignant (cancer) tumors- invades other tissues (metastasize)

*all tumors formed by increased cell formation or decreased cell death

Front 25

Define oncogenes

Back 25

overactivated proto-oncogenes

Front 26

Define proto-oncongenes

Back 26

induce cell growth or proliferation
inhibit cell death (anti-apoptotic)
increase cell number
gain-of-function mutations (overactivation), generally, one mutated allele

Front 27

Define tumor suppressors

Back 27

inhibit cell growth or proliferation
induce cell death (pro-apoptotic)
decrease cell number
loss-of-function mutations (inactivation)
both alleles must be mutated

Front 28

How are proto-oncogens get converted to oncogenes?

Back 28

-Radiation or chemical carcinogen causes mutation in coding and/or promoter region causing production of hyperactive protein and excessive expression of proto-oncogene
-gene rearrangement occurs, proto-oncogene is under control of strong promoter/enhancer
-proto-oncogene fused w/ another gene
-fusion protein is either overproduced or hyperactive

Front 29

Viral oncogenes associated w/ cancerous transformation of cells

Back 29

Papilloma virus-
proteins inactivate tumor suppressors RB & p53
causes cervical cancer
HTLV-1-
Tax protein is a coactivator of proto-oncogenes
HIV-
Tat transcription factor activates cytokine synthesis, promoting T-cell proliferation
causes non-Hodgkin lymphoma

Front 30

2 main pathways of apoptosis

Back 30

1. death receptor pathway
2. mitochondrial pathway
-both eventually activate the caspase cascade inside cell
-chromatin condenses, DNA fragments, cell shrinks & breaks into apoptotic bodies, bodies cleared out by macrophages

Front 31

How is Bcl-2 activated in follicular B-cell lymphoma

Back 31

-translocation moves Bcl-2 from chromosome 18 to 14 & places it under promoter control of immunoglobin heavy chain genes
-elevated Bcl-2 prevents death of B cells which leads to massive B-cell expansion=lymphoma

t(14;18)(q32;q21) chromosomal translocation

Front 32

Sources of the second hit in hereditary tumors (3)

Back 32

1. loss of heterozygosity
-loss of entire normal gene, deletion, non-disjunction, abnormal recombination
2. loss-of-function mutation
-in the normal allele, compound heterozygosity
3. epigenetic silencing
-of the normal allele

Front 33

Causes of mutations (3)

Back 33

1. carcinogens
2. radiation
3. UV-light

Front 34

what are carcinogens and what do they do?

Back 34

-chemicals that irreversibly modify DNA structure, usually metabolized in the human body first, modify DNA chem. structure

Front 35

How is G1/S transition controlled?

Back 35

Binding of cyclins activates the kinase activity of CDKs.
E2F (transcription factor, proto-oncogene) and Rb (retinoblastoma protein, tumor suppressor) are seperated by activated CDK complex. E2F goes on the increase gene transcription & cell-cycle progression

Front 36

What is the two-hit hypothesis?

Back 36

for inactivation of tumor-suppressor genes
-first hit:
germline mutation + somatic mutation (familial)
or
somatic mutation + somatic mutation (sporadic)
-second hit:
loss of heterozygosity
or
loss-of-function mutation
or
epigenetic silencing of normal allele

Front 37

What tumor suppressor gene class and protein are the following diseases associated with?
-Stomach cancer
-Neurofibrosarcoma
-Retinoblastoma, sarcomas
-most cancers
-breast cancer

Back 37

-stomach cancer: adhesion protein receptor. E-cadherin
-Neurofibrosarcoma: signal transduction, NF-1
-Retinoblastoma, sarcomas: transcription factor cell-cycle regulation, Retinoblastoma
-Most cancers: cell cycle/apoptosis, p53
-Breast cancer: DNA repair, BRACA 1

Front 38

What does retinoblastoma protein do normally?
What do mutation in the protein lead to?

Back 38

Retinoblastoma protein regulates the transmission from G1 to S phase

Mutations lead to retinoblastoma (retina cancer)

Front 39

What is a characteristic feature of retinoblastoma?
Is it a heritable or sporadic cancer?

Back 39

white reflection of the retina

the cancer has both heritable and sporadic form

Front 40

What does p53 do?

Back 40

p53 allows cell to undergo apoptosis if damage/stress is too great, or arrests the cell cycle until repair/correction is made if damage/stress is not too great

*mutation in p53 pathway almost always present in cancer

Front 41

Difference btwn initiator & execution caspases

Back 41

initiator (8,9,10)
-activated directly by the death cell receptor & mitochondrial pathways
execution (3, 6, 7)
-activated by initiator caspases
-cleave many diff proteins in cell, including actin, proteins of nuclear envelope, DNA repair enzymes & the inhibitor of caspase dependent endonuclease

Front 42

How is apoptosis regulated?

Back 42

depends on ratio of pro-apoptotic and anti-apoptotic molecules
-when pro-apoptotic molecules increase, more pro-apoptotic channel are functional, increasing CYM C release

Front 43

What does the formation of sporadic cancer require?

Back 43

multiple de novo mutations in diff oncogenes and/or tumor suppressor genes