1. Today: Chromosomes – information carriers
Cell division – daughter cells inherit a chromosome complement identical to that of the parent cell
Cancer - Things go terribly wrong

2. Positive and negative signals need to be balanced
A tightrope analogy: cells constantly respond and adapt to signals from their environment
Positive and negative signals need to be balanced
Normal controls on the cell cycle are disrupted in cancer

3. From chromosomes to cancer....
Chromosomes carry large numbers of genes
Normal cells are euploid – they have the expected number of chromosome sets in a karyotype (23 pairs of chromosomes in humans)
Aneuploid cells have abnormal numbers of chromosomes. Very few aneuploidies are viable, because gene products must be balanced for proper cell function
Cancer cells are characterized by MANY mutations that disrupt the balance in cells as well as chromosomal abnormalities

4. Human genome encodes ~21,000 proteins Chromosome Protein coding genes
Few human trisomies are tolerated – may relate to the number of genes that encode proteins
Human genome encodes ~21,000 proteins
Chromosome
Protein coding genes
Incidence at birth
% survival after 1 year 1
2102
13 (Pateau)
318
~1/15,000
<5%
18 (Edward)
268
~1/8000 21
225
~1/800
85% 22
431
very rare X
815
viable Y 45
X chromosome is subject to special regulation (more later)

5. Chromosome (structural) mutations involve blocks of genes
Some are large enough to be detected on karyotypes

6. Exchanges can also occur between chromosomes
Translocations can have severe effects
Number of euploid gametes is reduced

7. The Human Genome Project has revealed a surprising number of small deletions and insertions on every chromosome
We have probably underestimated human variation!

8. Daughter cells are identical copies of the parent cell
Cell Division
Daughter cells are identical copies of the parent cell

9. Mitosis (nuclear division) occupies a small fraction of the eukaryotic cell cycle
Interphase includes S phase and two gap (G1 and G2) phases
Chromosomes condense and become visible during mitosis
At the end of mitosis, two daughter cells will have the same chromosomes as the parent

10. Chromosomes decondense during interphase
Fluorescent technique based on DNA hybridization “paints” each chromosome a different color
Interphase
cell
Mitotic
chromosomes
Chromosomes decondense during interphase

11. A spindle provides the machinery for pulling the chromosomes apart
Theodor Boveri
mitotic spindle in an Ascaris egg
Boveri noted that the mitotic chromosomes split down their middle before they moved to opposite poles during mitosis

12. Spindle has fibers made of microtubules that move relative to another and change length during mitosis
spindle pole is the nucleation center for several sets of microtubules
Motor proteins provide the power

13. Prophase Chromosomes condense Nuclear membrane is intact
Spindle poles begin to organize outside the nucleus

14. Prometaphase
Nuclear membrane breaks down
Spindle fibers assemble

15. Metaphase Spindle is fully assembled
Chromosomes line up at the equator
Fibers connect centromeres to opposite poles
Force is equalized

16. Anaphase Chromosomes break at centromeres
Sister chromatids are drawn to opposite poles

17. Telophase Nuclear membrane reforms Chromosomes decondense
Cytokinesis (cell division)
Contractile ring separates daughter cells

18. Today we can watch mitosis in living cells and appreciate its precision
Mitosis explains the accuracy of genetic transmission

19. Mr. W’s Mitosis Rap

20. A disease of somatic (non germline) mutations
Cancer
A disease of somatic (non germline) mutations
Many mutations and chromosomal abnormalities are found in cancer
DNA sequencing is revealing the genes involved in cancer as well as the heterogeneity in tumors
No two cancers are the same!!! 1

21. Cells normally receive a host of signals from within and from other cells that tell them when to divide
Processing goes awry during cancer

22. Numerous checkpoints in the cell cycle
Are the chromosomes aligned properly on the spindle?
Numerous checkpoints in the cell cycle
Is the environment favorable for division?
Is the environment favorable? Nutrients? Hormones? Stressors?
Is the DNA replicated properly?
Is the DNA damaged?
Is the DNA damaged?
Cells that don’t pass checkpoints initiate a suicide pathway
Is the cell large enough?

23. Cells die by apoptosis – programmed cell death
(Greek: apo - from/off/without, ptosis - falling)
fragmented nuclei
membrane pinches off small fragments that other cells will ingest
apoptotic bodies in cytoplasm are evidence of self-digestion
18_17_arrest_checkpt.jpg
Rapid and leaves no trace
In adult tissues, the rate of cell death is equal to the rate of cell death