The Hallmarks of Cancer

Hanahan and Weinberg, Cell 100:57-70 (2000)

Cell Regulatory Networks Important in Cancer Cells

Hanahan and Weinberg, Cell 100:57-70 (2000)

Figure 8.3b The Biology of Cancer (© Garland Science 2007)

STARTor

Restriction Point

Figure 8.1 The Biology of Cancer (© Garland Science 2007)

Figure 8.6 The Biology of Cancer (© Garland Science 2007)

The Main Jobs of the Cell Cycle:

1. To accurately transmit the genetic information!

2. To maintain normal ploidy; i.e. diploidy!

Euploidy: additions of whole chromosome setse.g. n, 2n, 3n, 4n = haploid, diploid, triploid, tetraploid

Aneuploidy: additions or subtractions of one or more single chromosomese.g. 2n + 1, 2n -1, 2n + 2, etc.

Figure 8.4 The Biology of Cancer (© Garland Science 2007)

Properties Required for Transmission of Chromosomes During Cell Division

1. One and only one centromere

2. Functional telomere at both ends

3. Chromosomes must be fully replicated

4. Chromosomes cannot be too large or too small

S Phase of the Cell Cycle

Mitosis

Mitosis in an Early Fruit Fly Embryo

Figure 8.3a The Biology of Cancer (© Garland Science 2007)

Mitosis in NewtLung Cells

blue = DNAgreen = microtubules

Metaphase in a mammalian cell

Anaphase in a plant cell

G1-S and G2-M are the major control points in the cell cycle

Rao and Johnsoncell fusion experiments

1. Fuse M phase cell with interphase cell: Interphase nucleus enters M

2. Fuse S phase cell with G1 cell: The G1 nucleus enters S phase

3. Fuse S phase cell with G2 cell: The G2 nucleus does not enter S phase

Cyclin Dependent Kinases Regulate the Cell Cycle

Experimental Systems Important for Cell Cycle Studies

Arbacia punctulata

Xenopus laevisSchizosaccharomyces pombe

Saccharomyces cerevisiae

Fission yeast: Schizosaccharomyces pombe

Budding Yeast Saccharomyces cerevisiae

Isolating Temperature Sensitive Mutants in Haploid Yeast

Permissive (low) temperature Restrictive (high) temperature

Cdc Mutants Arrest at the Same Cell Cycle Phase

Phosphorylation of CDK Targets Changes Their Activity

Now performsa cell cycle function

cdc mutant growingat permissive temp (23C)

cdc mutant growth arrested after 6 hrs at non-permissive temp (36C)

The Behavior of a Temperature Sensitive cdc Mutant

How to Clone cdc Genes in Yeast

Cdc Genes Encode Proteins Needed for DNA ReplicationStudies in S. cerevisiae

Cdc Genes Encode Proteins Needed for the G2-M Transition:Studies in S. pombe

cdc2+ encodes a kinase Moreover = cdc28 in S. cerevisiae!

Cyclin was Discovered in Sea Urchin Embryos

ProteinLevel

Time

cyclin A cyclin B

M M M

can stimulate to

lay lots of eggs

mitosis mitosis mitosis

(Spisula is actually a clam.)

Overview of the frog life cycle

1 mm

spermtadpole feeds, grows

and becomes an adult frog

OOCYTE GROWS WITHOUT DIVIDING(MONTHS) FERTILIZATION

FERTILIZED EGG DIVIDES WITHOUT GROWING(HOURS)

The Maturation of Frog Eggs

The Maturation of Frog Eggs

An Assay for Maturation Promoting Factor (MPF)

Yoshio Masui, 1971

MPF Activity Peaks Before Each Cell Division

Moreover, MPF has kinase activity

Purification of MPF: The Birthof Cyclin Dependent Kinases

This is cdc2+!!(Cdc28 in

S. cerevisiae)

This is cyclin!!

Which = cdc13+

in S. pombe

Phosphorylation of CDK Targets Changes Their Activity

Now performsa cell cycle function

The Nobel Prize in Physiology or Medicine, 2001

“for their discovery of key regulators of the cell cycle”