BCB Lecture 2 09/15/2026

What are the two ways alteration of genes can occur

Gain of gene- oncogene
Loss of gene- tumor suppressors

What do oncogenes do

Accelerate cell cycle

What do tumor suppressors do

Prevent unwarranted proliferation and growth

Who were the fathers of the field of virology

Ivanofsky and Beijerinck

When was virology started

1890s

What did Ivanofsky discover

“filterable” infectious agents- ability to pass down noncellular traits

How did Ivanofsky and Beijerinck discover transferable non-cellular based traits

mashed tobacco, filtered through cheese cloth, filtered liquid had no cells under microscope, injected liquid into other plants, and plants formed nodule (plant cancer)

Who is Peyton Rous

Pathologist and virologist who won nobel prize for discovering cancer causing viruses in animals

What is the Peyton Rous story

farmer takes chicken with abnormal growth on leg to Rous. A lot of this farmer’s chicken had abnormal growths. Rous cuts off legs, mashes it, filters it, and injects it into 6 other chickens which then all develop tumors

Sarcoma

soft connective tissue cancer

What is Rous Sarcoma

first transferable cancer agent in animals

Who was Burkitt

Irish surgeon in British army field hospital that moved after war to post in Uganda and began to see children with facial tumors

What were the facial tumors that Burkitt was seeing in children

Lymphoma- specifically B-lymphoma

Lymphoma

soft tissue tumor

Who were Epstein and Barr

virologist and assistant that offered to use electron microscopy to look at tumors Burkitt sends them

What did Epstein and Barr find and how

found Epstein Barr Virus by culturing cells that fell off a tumor and doing electron microscopy

Epstein-Barr virus

first virus causing tumors in people

What disease does Epstein-Barr virus cause and how is it transmitted

Mono transmitted by saliva

How does EBV lead to B-lymphoma

EBV causes B-cell division until it is cleared unless you catch malaria which will continue the B-cell division

What were the two major groups of what causes cancer

Chemists vs Virologists

Who were Temin and Baltimore and what did they discover

Virologists that figured out life cycle of Rous Sarcoma Virus

What was Temin and Baltimore’s theory on the origin of oncogenes

Oncogenes have viral origin and viruses gave humans oncogenes

Who were Bishop and Varmus

Virologists that figured out Src gene was dispensable for virus life cycle

What was Bishop and Varmus’ theory on the origin of oncogenes

Oncogenes have a cellular origin

How did Bishop and Varmus find out oncogenes have a cellular origin

took RNA from virus and annealed to all animal DNA they could find- if bound then they knew the animal had Src genes which humans had

Why were oncogenes discovered before tumor suppressors

Viruses had oncogenes but they could not have tumor suppressors

What is the mechanism for why RNA viruses cannot have tumor suppressants

after an RNA virus inserts its DNA into the host genome, it needs to be transcribed and translated to reproduce more viral particles, if the viral genome contains a tumor suppressor, its transcription would inhibit host cell proliferation or induce cell death, which can interfere with viral replication

What are the three ways to make oncogenes

1. Point mutation

2. Gene amplification

3. Chromosome Rearrangement

Are the ways to make oncogenes mutually exclusive

no

Retinoblastoma

heritable tumor that is usually unilateral and easily dissectable

Two hit hypothesis

both alleles (copies) of a tumor suppressor gene must be mutated or inactivated for cancer to develop

How many mutations are required for an oncogene to cause cancer

one

What was the first real tumor suppressor discovered

Rb- retinoblastoma

DNA tumor viruses

group of viruses with DNA genomes that can change normal cells into cancer cells

What does human papillomavirus cause

cervical cancer and head and neck cancer

How does human papillomavirus cause cancer

Makes its own oncogenes that bind tumor suppressors

What is the role of Rb tumor suppressor

stop cell cycle by guarding entry into DNA synthesis

What is the definition of a Tumor Suppressor***

1. Loss of function mutations

2. Targeted allelic loss (methylation or deletion)

3. Inherited mutations that predispose to cancer

4. Somatic mutation in spontaneous tumors

5. Ability to inhibit transformed cells in vitro

Explain this part of the Tumor Suppressor definition “Loss of function mutations”

Must find loss of function mutations in this gene in the tumor, thus must identify normal function of gene to identify loss of function

Explain this part of the Tumor Suppressor definition “Targeted Allelic Loss”

Tumor suppressor can be turned off by silencing in most cases both alleles through methylation or deletion

What does the tumor suppressor Neurofibromatosis-1 inhibit

NF1 inhibits the oncogene Ras

What does the tumor suppressor PTEN inhibit

PTEN inhibits the oncogene PI3K

What does the VHL protein do

VHL degrades HIF (hypoxia inducer factor)

Mechanism of VHL loss to tumor growwth

• Expression of VHL results in HIF’s rapid degeneration

• Loss of VHL results in overproduction of vasculature

• Prolonged HIF expression and unregulated VEGF leads to tumors resembling haemangioblastomas

What does the tumor suppressor BRCA1/2 do

facilitates DNA repair

What does BRCA stand for

Breast cancer susceptibility locus

What is P53

tumor suppressor that is a transcription factor that acts on MDM2

What is unique about P53

it is the only tumor suppressor that does not follow the two hit hypothesis, only needs one hit to affect function

What is the #1 mutated tummor suppressor in all human cancer

P53

How does P53 work and how does its loss of function work

P53 sits on DNA as a tetramer, meaning only one of them needs to be mutated to interfere with function, this means 15/16 of the time there will be at least one bad P53

What type of mutation is a P53 mutation

dominant negative mutation

Dominant negative mutation

mutant allele product dominates over wild type allele product

Where do nearly all mutations of P53 occur

DNA binding Domain

What does the P53 tetramer need to sit on DNA properly

4 functioning DNA binding domains

What does CDK stand for

Cyclin dependent kinase

What are the CDK Inhibitors

p21, p27, and p56

What do the CDK inhibitors inhibit

CDK oncogenes

Why are CDK inhibitors not considered bonafide suppressors

Because they are redundant, thus they need six mutations/hits to pass it on genetically which is extremely unlikely, additionally, even if one completely loses function, it does not cause a cancer phenotype since the other inhibitors have overlapping function

What does the tumor suppressor Ink4a inhibit

CDK4/6

What does the tumor suppressor ARF inihibit

MDM2

What does CDK4/6 do

regulates entry into S phase

What does arf stand for

Alternative reading frame

What does Ink4a and Arf activation lead to

activation of Rb and P53

What exon do Ink4 and ARF share

Exon 2

What happens if Exon 2 of Ink4a/ARF gets mutated

both genes are knocked out and Rb and P53 get inhibited

What stimulates Ink4a/ARF

oncogenes stimulate this locus to apply emergency brakes

Why is the Ink4a/ARF locus set up like this

so tightly wound that transcription cannot happen, as it would be catastrophic during embryonic development if this occurred since it would stop cell growth and proliferation

What percent sequence do INK4a and ARF share and why are their gene products completely different

share 67% of sequence but are differnt because splice site for ARF shifts reading frame by +1