Genetics News• Helen Fillmore talks today on therapies

for neurodegenerative diseases. 12:30. Here.

• Problem Set 10 on line

On Our PlateGenetics of Cancer

• Clonal Nature of Cancer

• G6PD experiment

• Somatic vs. Germline Mutation

• RB: A Tumor Suppressor Gene

• Signal Transduction

• Oncogenes & Tumor Suppressors

• Progression of Cancer

Demonstration of Clonality

What does the gel represent? (e.g. DNA fragments?)

Protein with G6PD activity

Fig. 1: Analysis of glucose-6-phosphate dehydrogenase (G6PD) protein. Gel electrophoresis of protein samples, staining for G6PD activity. Protein for the left three lanes was taken from subjects with known genotypes. L is the protein sample from the leukocytes of the patient. S is a protein sample from skin cells of the patient. (Adapted from Fialkow et al (1969) Proc Natl Acad Sci USA 163:194-196)

Protein from LeukocytesProtein from Skin cells

What do “L” and “S” represent?

XBXB and XAXB

Demonstration of Clonality

SQ2 and 3: What is the mother’s genotype?

Why two genotypes?Which was she born with?

XAXB is the germline genotype

Demonstration of Clonality

SQ4: Why three bands in skin cells?

Lactate dehydrogenase???

1

3

3

1

8

1

2

1

4Glc-6-P dehydrogenase

Cancer: Infection or Clonal?

What is meant by “A”

and “B”?

Why do some cells have “A” and others have “B”?

Why do cells in panel

C have a mixture of cell types?

Why do cells in panel

B have the same cell

type? Fig. 2. Two models to explain cancer. ... Half of the cells have an active X chromosome carrying the A allele and half have an active X chromosome carrying the B allele.

Control over Cell Division

Mitosis

Gap1

DNA synthesis

Gap2

Control over Cell Division

Build up of signal(cyclin-CDK complex)

What happens if the cell is Rb-?

Hormones

phosphate

The Menace of Familial Retinoblastoma

Rb dominant

Mutation rare(say 1 in 109)

What is the result of a single Rb- mutation?

What about here?

Study Question 9

Cell #1: Suddenly loses eye pigment enzyme

Cell #2: Suddenly loses Rb

Normal retinal cells don’t divide

Derepressed cells divide once a day

Cell #1 Cell #2

Day 0Day 1Day 2Day 3Day 4

Ratio of Cell #1:Cell #2 after 30 days?

Study Question 8

•Loss of RB in retinal cells causes retinoblastoma

•Sporadic cases show tumors only in one eye

•Inherited cases show tumors occur often in both eyes

WHY?

Control over Cell Division

Build up of signal(cyclin-CDK complex)

Hormones

Signal Transduction:Environmental Signal

Signal Transduction:Activation of Receptor

Signal Transduction:Activation of Protein Kinase

Ras

Signal Transduction:Activation of 2nd Protein Kinase

Signal Transduction:Activation of 3rd Protein Kinase

Signal Transduction:Activation of Transcription Factor

E.g. Myc

Signal Transduction:Activation of Genes

Signal Transduction:Activation of Receptor

No hormone

Mutant signaltransducing protein

(e.g. Ras)

Signal Transduction:Activation of Genes

No hormone

Mutant signaltransducing protein

(e.g. Ras)

Control over Cell Division

Build up of signal(cyclin-CDK complex)

p53

Hormones

Mismatch Repair

Suicide?(Apoptosis)

Control over Cell Division

Build up of signal(cyclin-CDK complex)

Hormones

Oncogene vs Tumor Suppressor

OncogenesWhen mutated, stimulates cell division

• RAS - Stimulates protein kinase

• MYC - Transcriptional factor

Tumor suppressorsWhen mutated, releases division to cell block

• RB - Inhibits transcription factor

• P53 - Many functions (e.g. transcription factor)

Study Question 12

• Protein monitors DNA for DNA damage

• If DNA damaged, protein blocks cell division

Is protein tumor suppressor or from an oncogene?

Study Question 15

Lots of p53 mutations in dead people. WHY?

A. p53 is prone to mutation?

B. p53 is not prone to mutation, but leads to death?

C. p53 related to feedback?

Study Question 15

A B C D

Causes of Particular Cancers

Study Question 13

Why does the chromosome 8/14 translocation lead

specifically to lymphomas?

What is myc? What’s its threat?

What is Pimm? Where is it on?