Lecture 32

Question 1

List and define the 2 Tumor suppressor Gene types (3 and 2)

Answer 1

1. proteins the normally restrict cell growth and proliferation

proteins that inhibit progression through G1/S in cell cycle ex. Rb CKI’s

Receptors/components of singalling pathways that inhibit cell proliferation

Proteins that promote apoptosis ex. caspases

2. proteins that maintain the integrity of the genome

checkpoint control proteins that detect DNA damage and stop the cell cycle ex. ATM, ATR

DNA repair enzymes or pathways

Question 2

Compare hereditary vs. non-hereditary retinoblastoma

Answer 2

hereditary: 40% of all retinoblastoma and both eyes are usually affected (defect in all cells)

have only one good Rb gene, so it takes one somatic event to cause cancer via LOH

Non-hereditary: 60% of all retinoblastoma and usually only 1 eye affected

“2 hit hypothesis” that requires 2 mutation events to cause cancer (defect in only cancerous cells)

Question 3

What is the main difference between proto-oncogenes and tumor suppressor genes?

Answer 3

proto-oncogenes (gas pedal) form cancerous oncogenes from a SINGLE (dominant effect) mutation event and cause uncontrolled proliferation

tumor suppressor genes (brakes) cause cancer after TWO (recessive effect) mutation events that make the cell unable to effectively regulate cell proliferation

Question 4

Describe Bcl2 in terms of what it is, how it was discovered, and a common issue it is involved in.

Answer 4

was the first discovered oncogene (found in B-cell lymphoma) that inhibits apoptosis

in B-cell lymphoma, Bcl2 expression is increased after a chromosomal translocation event

Question 5

List and describe the function of the 2 viral proteins of the papilloma virus

Answer 5

both cause uncontrolled replication

E6: binds to p53 and inactivates it (this means no CKI’s are produced to control Cdk and cyclin activity)

E7: binds to Rb and inactivates it (this means E2F can cause over-expression of G1/S-Cdk and S-Cdk)

Question 6

describe colorectal cancer in terms of it’s detection/treatment, and the most important loss of function mutation that usually occurs in it’s pathology.

Answer 6

one of the most preventable cancers (detect via colonoscopy) and it takes 10 years for tumor progression to occur

Polyps are precursors of colorectal cancer, that should be surgically removed before they become malignant tumors

Apc mutations are the most important loss of function mutation that t causes colorectal cancer

Question 7

state 3 cancer treatments

Answer 7

best weapon is early detection

Chemotherapy, especially chemotherapy cocktails are also found to be decent treatments

Gleevec can effectively treat Chronic myelogenous leukemia

Question 8

Rb pathways that lead to cancer feature both proto-oncogenes and tumor suppressor genes. explain the tumor suppressor gene portion of this. (general definition and 2 methods)

Answer 8

CKI or Rb genes are tumor suppressor genes (CKI and Rb issues can cause cancer)

Loss of CKI means there is no control over Cdk and cyclin activity

Loss of Rb means there is no suppressor on E2F (so the cell enters the cell cycle too often)

Question 9

List the 4 processes that p53 (bad ass tumor suppressor gene) is involved in.

Answer 9

cell cycle arrest at checkpoints

DNA repair

apoptosis

blocking angiogenesis to cancerous tumors

Question 10

When p53 is acting as a gene regulatory protein, describe the 2 main functions it has and why those prevent cancer.

Answer 10

p53 stimulates the transcription of the p21 (CKI) gene. p21 binds to G1/S-Cdk’s and S-Cdk’s in order to stop the cell cycle

p53 also activated expression of pro-apoptotic proteins BH123 activates and BH3-only

(BH123 aggregates in outer membrane of mito and release cytochrome c to cause apoptosis)

(BH3-only inhibits anti-apoptotic Bcl2 from inhibiting the aggregation/activation of BH123)

Question 11

When Viruses cause tumors, describe the differences in the way that benign growths and malignant tumors are formed

Answer 11

Both are caused by viral DNA integrating it’s DNA into the host’s DNA

if the integrated viral DNA interferes with the host’s ability to control cell division, malignant tumors develop

If the viral proteins mediate controlled replication of the virus, then benign growths/warts occur

Question 12

Define “oncogene collaboration” and give an example of it in mice

Answer 12

oncogene collaboration: when 2 different oncogenes work together to cause more severe tumor development

Myc Tg x Ras Tg mice develop tumors earlier and more quickly than just Myc Tg mice or Ras Tg mice

Question 13

state the “cancer treatment strategy” of chemotherapy use

Answer 13

give as strong a dose as possible to kill the tumor and almost kill the patient

Question 14

Describe FAP colorectal cancer and what it is caused by

Answer 14

FAP = Familial adenomatous polyposis coli

causes hundreds of polyps which inevitably leads to one of them becoming malignant

causes by the inactivation of the APC tumor suppressor gene

Question 15

Describe HPNCC colorectal cancer and why it stands out from the other types of colorectal cancer. Describe how HPNCC forms such an odd presentation.

Answer 15

HPNCC = Hereditary non-polyposis colorectal cancer

most HPNCC cells have a normal # of chromosomes, which make it tough to detect early

This odd presentation of cancer is caused by DNA mismatch repair

Question 16

Describe how Bcr-Abl genes form, what they cause, and what Gleevec does to them.

Answer 16

Bcr-Abl genes are formed by a translocation between chromosomes 9 and 22

they cause CML (chronic myelogenous leukemia) when they fuse together on the same chromosome

Able is a tyrosine kinase and it’s fusion with Bcl makes it hyperactive (which causes cell proliferation)

Gleevec inhibits tyrosine kinase activity by blocking the activity of Bcr-Abl proteins (via mimicking ATP)

Question 17

Briefly explain personalized cancer therapy techniques

Answer 17

the gene expression profile of a patient is determined via DNA microarray and cancer critical genes are identified

treatment is then tailored for that patient’s unique cancer risks

Question 18

describe anti-angiogenesis therapy

Answer 18

basically “starve” tumors by preventing the angiogenesis function of cancer cells (cant grow without nutrients via the blood)

Question 19

State the 4 occurrences that can activate p53 activity, considering a cell has properly functioning p53 gene

Answer 19

Hyper-proliferative signals

DNA Damage

Telomere shortening

Hypoxia

Question 20

what is p16?

Answer 20

p16 is a CKI that binds to a Cdk-cyclin complex that would otherwise phosphorylate Rb

phosphorylated Rb has a much lower affinity for E2F, and therefore a phosphorylated Rb would allow E2F activity (causing S-Cdk action by making more cyclins for it)