Lecture 47: Oncogens

Question 1

Tumor Progression

Answer 1

Progression (Spreading):
Normal->Hyperplastic->Dyplastic-> Neoplastic->Metastatic
(Metastatic= affects basement membrane)

• Progressive aggressiveness
• Wave of mutation followed by clonal expansion

Question 2

Risk factors of cancer

Answer 2

-increased age

but some cancers can be more common in kids

Question 3

Monoclonality

Answer 3

-Cancer arises from single cell that proliferated

Evidence:
1) Examanincation of X-inactivation pattern in cancer
(All cancer cells have same copy of intactivated chrom)

2) All Chrom carry the same chrom abnormalities
3) Multiple myeloma produce monoclonal immunogloulin (produce same antibody immunoglobulin = one single dark band)

Question 4

Changed for Cancer formation

Answer 4

1) Proliferation without external stimuli
2) Ignores growth inhibition
3) Switch to aerobic glycolysis = energy = rapid growth
4) Resist apoptosis
5) Unrestricted proliferation capacity
6) Angiogenesis = new blood vessels = nutrients to divide
7) Loss of cell to cell adhesion = can invade
8) Evasion of the immune system

Question 5

Where do mutations occur to create cancer?

Answer 5

1) Proto-oncogenes
- Encode products for cell growth = excessive gene = gain of function

2) Dna Repair Genes
- Impairs the cells ability to recognize and repair nonlethal genetic damage

3) Tumor Supressor Genes
-Usually Inhib cell growth
Mutation = can’t inhib cell growth = loss of function

4) Apoptosis Regulating Genes
- Gain of function: Suppress apoptosis
- Loss of function: Promotes apoptosis

Question 6

Major Cellular Proliferative Pathway (MAP Kinase Pathway) Under normal physiologic Condition

Answer 6

1) Growth factor outside the cell
2) GF binds to GF receptor
3) Receptor autophosphorylation
4) Exchange GTP for GDP on RAS
5) RAS binds to RAF, phosphorylation cascade
3) Up/downregulation of transcription for cell survival and proliferation

Question 7

Oncogenes in Major Cellular Proliferative Pathway (MAP Kinase Pathway)

Answer 7

-Proto-oncogenes promote cell growth, mutations = decreased regulation = excess proliferation

Proteins that can get mutated:
1) Growth factors

2) Growth factor receptors
- c-erbB: EGF receptor kinase (transmembrane)

3) Intracellular Tyosine Kinases
- c-abl: Cytosolic (Cytoplasmic)

4) G Protein/Signal transduction
- c-ras: GTP-binding protein (Membrane associated)

5) Transcription Factors (All nuclear)
- c-myc: HLH protein
- c-fos: Leucine zipper protein
- c-jun: Leucine zipper protein

Question 8

Growth Factor (Tyrosine Kinase) Receptor Activation

Answer 8

1) GF binds to receptor tyrosine kinase
2) Activation of receptor
3) Conformational change to active dimeric state
4) Autophosphorylates tyrosine residues

Question 9

How are oncogenes activated by gene amplification?

Answer 9

1) Duble minutes
2) Homogeneously staining regions

(HSRS = amplified oncogenes attached to the chrom)

Question 10

How are oncogenes activated by gene amplification?

Answer 10

1) Double minutes
-Extrachrom fragments of DNA w an amplified oncogenes
(Can see with FISH)

2) Homogeneously staining regions (HSR)
-Amplified oncogenes attached to the chrom
-Mutation in N-MYC (transcription factor)
(Can see with FISH)

-Both result in overproduction of oncoprotein = increased cell division

Question 11

Point mutations causing Oncogenic Activation of Growth Factor Receptors

Answer 11

• ERBB1 = encodes for EGFR, epidermal growth factor
• Point mutations in ERBB1 = constituitive activation of EGFR tyrosine kinase –> Lung adenocarcinomas
• Inhibs of ERBB1 = therapy for these lung cancer pt’s

Question 12

How did a chrom translocation lead to Chronic myelogenous Leukemia?

Molecular therapy?

Answer 12

Chronic myelogenous Leukemia:

• Translocation the ABL gene chrom 9 (normal position) –> chrom 22, next to BCR =activation of ABL
• Causes the fusion of gene BCR-ABL, which encodes for a continuously active nonreceptor tyrosine kinase, which activates the signaling pathway of receptor tyrosine kinase

Therapy:
-Imatinib mesylate (Gleevec) = BCR-ABL tyrosine kinase inhibitor = suppresses tumor proliferation

Question 13

How did a chrom translocation lead to burkitt’s lymphoma?

Answer 13

-8:14 translocation = C MYC increased expression bc under regulation of IgH (active promoter) = cell growth (G1/A phase)

Question 14

Activation of Ras proto-oncogenes

Answer 14

Ras= GTPase in MAP-Kinase (cell prolif pathway)

• Ras-GTP = activated growth pathway
• Ras-GDP = inactivated (No growth)
• Many mutations inhib GTPase activity making it continuously active = cell prolif
• Single point mutations at Gly12 and Gln61 = continuously active Ras = cell prolif