Cell Reproduction: Mitosis and Cancer
February 25, 2004

Readings: Starr Ch. 8, p 126-136. CD-ROM: excellent diagrams and a cool mitosis movie!
Caution: Heavy terminology ahead! Before you begin reading, you may want to write the definitions for these words down: Somatic cell, Germ Cell, Diploid, Haploid, Chromosome, Sister Chromatid, Homologue
(Homologous Chromosome)
Warm Up 6 and Good For 6 due this week!

I. Multicellular organisms constantly need to make more cells!

II. Preparing for Cell Division: Dividing the DNA equally into 2 cells

Overview: before a cell can undergo mitosis, is has to do one VERY important task: Copy all of its chromosomes by the process of DNA replication so that each new cell will get its own complete set of chromosomes. This process happens BEFORE a cell gets ready to divide, in the "S-phase" ("Synthesis-phase") of the cell cycle.

Chromosomes: are found in the nucleus of cells and are made of DNA. An individual chromosome is one, l...o...n...g... DNA molecule which is highly coiled and condensed around histone proteins. Each chromosome contains a few thousand genes, that "code for" all cellular proteins, and is usually millions of base pairs (A-T, C-G) long.

Humans have 46 chromosomes in all of our somatic (body) cells. Lining these chromosomes up by size and shape (karyotyping them), it is apparent that the 46 chromosomes are actually 23 pairs of chromosomes.One of each pair was originally from "mom" and the other from "dear 'ol dad". Organisms that have paired chromosomes (also called homologous chromosomes, or homologues) are said to be diploid (or "2n" - 2 copies of each chromosome). Every time our body cells (somatic cells) divide, each NEW cell must also end up with these same 46 (23 pairs of) chromosomes. This is the goal of mitosis - to make sure that every cell ends up with 23 pairs of chromosomes after cell division.

This figure is an example of a human karyotype: 23 pairs of homologous (paired) chromosomes (including the homologous 'sex' chromosomes - in this case X and Y = this is a baby boy)

III. DNA Replication - Copying the DNA during S-Phase

Every time one of our cells divides by mitosis, our DNA first has to be replicated - copied - so that each new cell can receive a complete set of 46 chromosomes.. In fact, 3 billion bases have to be copied precisely in 4-6 hours!!!! How does this event occur?? The DNA double helix is perfectly suited for replication because each strand can serve as a template (mold) to produce a shape opposite to itself.

A cast of enzymes and proteins accomplish DNA replication:

1. The two strands of DNA are "unzipped" (bonds broken between bases) by the unwinding enzyme DNA helicase (A).

2. New nucleotides are inserted by complementary base pairing (A to T, C to G etc) by the enzyme DNA polymerase (B) in the replication fork.

3. New nucleotides are linked together at their sugar-phosphate groups by the enzyme DNA ligase, forming a new double helix from one strand of "old" and one strand of "new" DNA. Because the DNA molecule contains one new strand and one old strand, the replication process is termed semi-conservative (don't need to know the details).

4. DNA repair enzymes "proofread" and correct mistakes

5. DNA is organized on a protein "scaffold": Each chromosome is one giant molecule of DNA millions of base pairs long. If stretched out, this would equal ~1 yard of DNA per cell! Histone proteins (C) bind tightly to DNA and keep the chromosomes wound up tightly around "spools" of histones called nucleosomes.

6. After DNA replication, each replicated chromosome is then composed of two identical parts - each copy of DNA is called a sister chromatid, held together by a centromere. The chromatids need to stay together to keep things "organized" in the cell. There are 46 of these replicated chromosomes after DNA replication

After DNA Replication (but before mitosis) - This figure shows 2 duplicated chromosomes after DNA replication, each consisting of 2 identical double helixes, seen as sister chromatids.

DNA replication: now see the movie! Or two:

IV. The last part of the cell cycle: M-phase, or Mitosis

Mitosis: How 1 cell becomes 2 cells: During mitosis (division of the nucleus), the sister chromatids made during S-phase are pulled apart., and partitioned into the 2 new daughter cells by cytokinesis (division of the cell). And all in 5 convenient steps! Note: these steps are 'artificial' in that mitosis is a continuous process, it does not 'stop' at these stages, but proceeds smoothly through. However, it is convenient for us to think of it in steps!

It is easiest to think of each step using a simple, 2-word phrase:

The end result of mitosis = 2 daughter cells, genetically identical to the parent cell.
Mitosis Movies: Animation, OK, another animation, and a real cell !

V. Cancer: renegade cells escaping the controls on cell division:

1. What is cancer? Cancer is essentially a disease of mitosis - the normal 'checkpoints' regularing mitosis are ignored or overriden by the cancer cell. Cancer begins when a single cell is transformed, or converted from a normal cell to a cancer cell.

Often this is because of a change in function or a DNA mutation that occurs in one of several genes that normally function to control growth. Examples:
(1) the p53 gene, the "guardian of the genome", usually functions to properly control the cell cycle. However, p53 is mutated in over 50% of all human cancers.
(2) the BRCA 1 gene, the "Breast Cancer Gene" normally functions to supress tumor formation; but if a gene contains mutations such that BRCA1 does not work properly, tumor formation can begin (Note: mutations in this gene do not mean that a person will develop breast cancer, just that they have an increased risk for breast cancer).

Once these crucial Cell Cycle genes start behaving abnormally, cancer cells start to proliferate wildly by repeated, uncontrolled mitosis.

2. Tumors - Good Cells gone Bad...?
The cancer cells proliferate to form mass of cancer cells called a tumor. As the tumor grows larger, it begins to release proteins from the cell to attract new blood vessel growth (this is called angiogenesis). At point the tumor contains ~ 1 million cells and is about the size of a 'bb'.

Benign: tumor cells remain at original site. Can be removed surgically or killed by radiation, usually eliminating any further cancer development at that site.

Malignant: some tumor cells send out signals that tell the body to produce a new blood vessel at the tumor site. These cells not only have their own food and oxygen supply, they also have an avenue for escape to a new part of the body - through the new blood vessel and into bloodstream. Cells that break away from the tumor begin to spread to surrounding tissues (via the bloodstream or lymph) and start new tumors = metastasis. Usually surgery is performed to remove the tumor, followed by radiation and chemotherapy.

So, why do chemotherapy drugs cause a person's hair to fall out? See this week's WarmUp!

3. Unusual features of Cancer Cells.

(1) Cancer cells are frequently "immortal": whereas normal cells divide about 50 times and them die, cancer cells can go on dividing indefinitely if supplied with nutrients (A common laboratory cell line, HeLa cells, was originally isolated from a tumor in 1951 and is still growing).

(2) Cancer cells often have unusual numbers of chromosomes or mutations in chromosomes. Aging (production of toxic oxygen "free radicals"), exposure to toxins (like components of tobacco tar), mutagens (like ultraviolet light) all cause mutations in genes and cancer; but normal errors in DNA replication can lead transformation of the cell if they occur in a crucial gene.

(3) Cancer cells may also have an abnormal cell surface; instead of "sticking" to its neighboring cells, cancer calls tend to "round up" and break attachments its neighbors cells, allowing for metastasis.

(4) Cancer cells ignore the usual
density-dependent inhibition of growth in cell culture (or in body tissues), multiplying after contact with other cells are made, piling up until all nutrients are exhausted.

Stopping cancer cell growth:

Chemo Drugs that stop DNA synthesis/ replication:

Chemo drugs Taxol and Vincristine, both natural products from plants, work by inhibiting spindle fiber formation and disrupting mitosis. No mitosis, no new cancer cells!

Drugs called angiogenesis inhibitors, discovered by Dr. Judah Folkman (Nobel prize in his future?) prevent metastasis, but are currently in human Clinical Trials. Stay tuned!

Objectives: 2/24/03 After this lecture, you should be able to:

1. Draw or describe the phases of the cell cycle: G-Phase, S-Phase, and M-Phase (and what happens in each)
2. Describe a chromosome and contrast it with a sister chromatid.
a. How did it get to BE a sister chromatid?
b. Why do the sister chromatids stay joined together?
3. Explain how DNA is 'unzipped' and replicated. What is the function of DNA helicase, DNA ligase, DNA polymerase, and DNA repair enzymes? What do Histone proteins do?
4. Draw and describe each phase of mitosis (you will see this again, hint hint...)
5. Describe how a normal cell can be transformed into a cancer cell
6. Explain the 4 unusual features of cancer cells.