Chapter 4

Do most types of human cancers act like an infectious disease?

Do most types of human cancers act like an infectious disease?

No, because they do not spread from one individual to another like an infectious disease

Which 2 tumor types in the western world could clearly be tied to viruses?

•Cervical carcinomas

•Hepatomas (liver carcinomas)

T or F: during the 1970s attempts to isolate viruses from human tumors was mostly successful

False

Transfection

technique to introduce naked DNA into mammalian cells

What did extensively studying infectious agents uncover?

studying these infectious agents uncovered many cellular oncogenes (proto-oncogenes) and tumor suppressor genes

Do cellular oncogenes exist in transformed cells?

No because 3-MC converted previously normal genes into mutant alleles that function as oncogenes

How did they figure out whether or not transformed cells have cellular oncogenes?

Chemically transformed mouse fibroblasts - treated repeatedly with carcinogen and mutagen 3-methylcholanthrene (3-MC) - component of coal tars

What is 3-MC

mutagen 3-methylcholanthrene (3-MC) - component of coal tars

True or False: Cells derived from human carcinomas capable of transforming mouse fibroblasts

True

Can oncogenes work across species to induce cell transformation

Yes

What cancer was amplification of erbB-related gene seen in?

Breast Cancer

What is the relationship between the increase in gene copy number and survival rate

Increase in gene copy number of more than 5 copies per cancer cell correlated with a decreased number of patients who survived

What was the conclusion to this experiment?

3-MC converted previously normal genes into mutant alleles that function as oncogenes

Which picture shows abnormal cells?

The left shows abnormal appearance of the cells in the focus

Which picture shows normal cells?

-The right shows normal cells.

-They are untransformed cells outside of the focus

True or False: oncogenes work across species to induce cell transformation

True

What does this picture show?

Transfection of DNA from the T24 human bladder carcinoma cell line

True or False: Cells derived from human carcinomas are not capable of transforming mouse fibroblasts.

False

Are oncogenes carried by transforming retroviruses related to oncogenes discovered in human tumor cell lines?What

Oncogenes discovered in human tumor cell lines are related to those carried by transforming retroviruses

What technique is used to detect gene amplification in other tumors?

FISH

Fluorescence in situ hybridization (abbreviated FISH) is a laboratory technique used to detect and locate a specific DNA sequence on a chromosome.

Amplicon

unit of DNA amplification

When erB2/HER2 is amplified, what happens to closely linked (nearby) genes?

They are also amplified

Are co-amplified genes important in establishing the cancer cell phenotype?

yes

Are all cancers localized to 1 or 2 chromosomes?

No, some some cancers have altered transcripts in many chromosomes

Are the oncogenes originally discovered through their association with retroviruses normal?

No, many of the oncogenes originally discovered through their association with retroviruses could be found in a mutated, activated state in human genomes

When can proto-oncogenes be activated?

Proto-oncogenes can be activated by genetic changes affecting protein expression or structure

What are ways gene amplification can be achieved?

• Retroviruses altering the promoter region of a gene and turning it on constitutively (constant)

• By other regulatory molecules in cancer cells

• Single base substitution identified  in H-ras oncogene

• Chromosomal Translocation

• Structural changes in proteins- growth factor receptors

True or False: Gene amplification can only be caused by retroviruses altering the promoter region of a gene and turning it on constitutively

False, there are many ways genes can be amplified

Where is H-ras found?

•present in bladder carcinoma as a single gene copy

•Mutated version of this gene was detected in bladder carcinoma cells

True or False: changing one nucleotide won’t convert a normal gene to an oncogene

False: G→T point mutation responsible for converting H-ras (normal gene) into a potent oncogene

What is the first mutation discovered that lead to neoplastic growth of a human cancer?

G→T point mutation

Where did the point mutation occur in H-ras oncogene?

Reading frame

Reading frame

A nucleotide sequence is read 3 nucleotides at a time (codons) starting at a start codon

What does this picture show?

A point substitution can change a proto-oncogene into an oncogene

In the H-ras gene what amino acids get switched?

Substitution of glycine for valine in the protein

What does this picture show?

K-ras oncogene sequencing revealed that most mutations result in amino acid substitutions in residue 12

True or False: tumors that carry the ras oncogene don’t amplify the mutated gene

False

• Many animal and human tumors that carry the ras oncogene also amplify the mutated gene

• structure of the protein is affected and also the regulation of the protein/gene is altered

What is Anopheles gambiae mosquito a vector for?

vector for malaria

What are the causes of Burkitt’s lymphoma?

• malarial infection

• presence of Epstein Barr virus (EBV)

What did the tumor cells of Burkitt’s Lymphoma carry?

• Tumor cells carried chromosomal translocations (region of one chromosome breaks off and then fuses with another chromosome)

What did the translocations in Burkitt’s lymphoma do?

These translocations separate the myc gene from its normal transcriptional promoter and place in under the control of a highly active transcriptional regulator

Are translocation mutations somatic or germ line?

Somatic

What can translocations lead to ?

Hybrid mRNA

How do translocations liberate mRNA?

Because hybrid mRNA can NOT be targeted miRNA, it will not get degraded and just keep on increasing

What happens when mutations lead to structural changes in growth factor receptors?

When a receptor is mutated and doesn’t have a extracellular domain (top of receptor that attaches to ligand) it will still emit signals causing the cell to grow and keep dividing

What does this picture show?

It shows what happens in a normal cell with a functional growth factor receptor vs the mutated one

What does this picture show?

Formation of a hybrid protein in CML

How does gene amplification in breast cancers correlate with survival?

Gene amplification lowers survival rate

Why is it significant if a point mutation happens in a reading frame?

If a mutation disrupts this normal reading frame, then the entire gene sequence following the mutation will be incorrectly read. This can cause changes in amino acid sequences, proteins, and structure.

What are the two main etiological factors identified in Burkitt’s Lymphoma?

EBV and malaria

1.All of the following are proto-oncogenes/oncogenes except _______

A. myc

B. ras

C. HER2

D. RISC

D

What effects can translocation have to drive cancer cell transformation?

• In Burkitt’s lymphoma, the translocations separate the myc gene from its normal transcriptional promoter and place in under the control of a highly active transcriptional regulator

• Can cause hybrid mRNA which wont be targeted by miRNA and won’t get degraded, increasing the proliferation

• Translocations in human tumors that deregulate proto-oncogene expression and create oncogenes