Medical Genetics Viii: Cancer Genetics

Front 1

List the phases of the cell cycle in order.

Back 1

M
G1
S
G2

Front 2

Describe the regulation of the cell through the cell cycle.

Back 2

The cell cycle is controlled by positive and negative regulartory circuits that ensure that critical cell cycle processes, such as completion of DNA syntehsis and proper spindle formation have been completed succesffully. If tthis is the case, the cell is permitted to progress through the checkpoint and initiate the next stage of the cell cycle

Front 3

What enzymes control passage through the cell cycle?

Back 3

Cyclin-dependent kinases (Cdks).

Front 4

Define: Programmed cell death.

Back 4

Apoptosis

Front 5

Describe four ways that the activitiy of the CDKs are controlled?

Back 5

1. Phosphorylation of residues in the Cdk itself that either promote or inhibit catalytic activity
2. regulated degradation of cyclins
3. Regulated synthesis of cyclins and Cdks
4. Inactivation of Cdks by binding specific protein inhibitors

Front 6

Studies of a variety of cancers demonstrate tha multiple genetic alterations are usually required for a cell to escape these regulatory circuits and become malignatn. This is known as the ______ origin of ________.

Back 6

Multistep origin of cancner

Front 7

Why are checkpoints important?

Back 7

They provide an arresting point to complete the process of division or synthesis and a quality control mechanism.

Front 8

What is the relationship between apoptosis and checkpoints?

Back 8

If the DNA damage is so extensive, apoptosis may be initiated when the cell is arrested at one of these checkpoints.

Front 9

What occurs when cyclin-dependent kinases form complexes with regulatory proteins termed cyclins?

Back 9

When complexed with cyclins, Cdks phosphorylate a large number of different protein substrates, including both structural proteins and regulatory proteins.

Front 10

Which two genes are most often mutated in human cancers?

Back 10

p53
Rb

Front 11

What is the function of p53 and Rb genes?

Back 11

These genes regulate the ability of teh cell to pass the G1 to S phase checkpoint and commit to cell division.

Front 12

Define: a normal cellular gene involved in stimulating cell division or proliferation.

Back 12

Proto-oncogenes

Front 13

Define: a dominant gain of function mutation that converts normal cellular genes involved in stimulating cell division or proliferation (proto-oncogene) into a form that promotes unregulated growth.

Back 13

Oncogene

Front 14

Define: A gene which normally acts to repress cell proliferation.

Back 14

Tumor suppressor gene

Front 15

What is the molecular basis for Burkitt lymphoma?

Back 15

A translocation which combines 8 and 14 chromosomes to form t(8;14) juxtaposes the transcriptional enhancers of the highly active promoter of the immunoglobulin heavy chain gene to the coding region of the myc growth control gene.

Front 16

What is the molecular basis for chronic myelogenous leukemia (CML)?

Back 16

A translocation creating t(9;22) or the Philadelphia chromosome.

Front 17

Define: A disorder of hematopoietic stemm cells whth a t(9;22) chromosome.

Back 17

Chronic myelogenous leukemia

Front 18

What is the significance of the philadelphia t(9;22) on CML?

Back 18

The t(9;22) translocation fuses the introns of two differnt genes, BCR and ABL. This allows splicing between the BCR and ABL exons, leading to the production of a hybrid protein that contains portions of BCR and ABL. The hybrid protein is a constitutively active tyrosine kinase that causes unregulated activation of cell growth pathways.

Front 19

List the steps of the transfection assay.

Back 19

Normally, cells stop growing when they touch. In this assay, human tumor DNA is put onto a plate with mouse cells. The mouse cells which take up the oncogene will NOT stop growing and will clump together resulting in foci. The dna in these foci is purified and the gene is isolated.

Front 20

List two proto-oncogene protein products.

Back 20

PDGT: Platelet-derived growth factor
EGFR: Epidermal growth factor receptor are membrane growth factors

Front 21

List the types of proto-oncogenes.

Back 21

Signal transduction
Secreted growth factors
Membrane-bound growth factor receptors
Cytoplasmic signaling proteins
nuclear transcription factors.

Front 22

What is the difference in the inheritance of familial retinoblastoma with sporadic retinoblastoma?

Back 22

Sporadic retinoblastoma arises when, by chance, both copies of the RB1 gene have been inactivated by somatic mutation. This should be rare, because it depends on the occurrence of two low frequency events in the smae cell. In the familial form, an inherited mutation inactivates one copy of the RB1 gene. The other copy of the gene is normal, and indeed most of the retinal cells do not form tumors. Due to germline mutation, theese cells have taken the first step toward malignancy.

Front 23

What is the two hit hypothesis or Knudson hypothesis for retinoblastoma?

Back 23

It takes two low frequency events to inactivate both copies of the RB1 gene.

Front 24

What is the normal function of RB1?

Back 24

RB1 plays a critical role in regulating the progression of cells through the cell cycle. It binds animportant transcription factor that directs the transcription of genes for enzymes inovled in DNA syntehsis. When bound to RB1, the transcription factor is inactive and DNA syntehsis is blocked. When RB1 is phosphorylated by CDKs, it rleases the transcription factor and DNA synthesis can proceed. In the absence of RB1, transcription factor activity is not regulated by the cell cycle.

Front 25

What is the normal funciton of p53?

Back 25

p53 is a transcription factor, in part by senseing DNA damage and possibly other stresses. When damaged DNA is present in the nucleus, active p53 promotes the trnascription of a CDK inhibitor. This inhibitor prevents the CDK from phosphorylating $B1, which in turn prevents DNA synthesis from initiating.
p53 can also cause the cell to initiate apoptosis after extensive DNA damage has occurred.

Front 26

True/False: p53 mutations are present in virtually all tumors, familial and sporadic.

Back 26

True

Front 27

What effect does a mutation in BRCA1 or BRCA2 have on the risk of breast cancer?

Back 27

Significantly increase the isk of breast cancer; interestingly they also significantly increase the ris for ovarian cancer in women.