CELL CYCLE

 

I.              Reproduction is a unique feature of life and cellular reproduction is the basis of  that process.

A.      For a cell to reproduce it must go through certain steps:

1.      There must be a cue that tells the cell to divide. We know this is not simply a lapse of time but involves internal and/or external signals.

2.      All cellular components must increase to accommodate two cells instead of one. This includes the fact that the DNA must replicate.

3.      That DNA must be divided into two new regions (segregation). The cellular components must also be segregated.

4.      Cytokinesis: The cell membrane (and cell wall, if existent) must  reorganize (may involve growth) to create two new cells.

B.      Eukaryotic cell cycle is different than prokaryotic.

1.      Prokaryotic DNA replication starts at the Œori¹ site at the membrane attachment and proceeds around the circular DNA forming two interlocking bands that must separate (more on this later). Cytokinesis occurs by fission.

2.      Eukaryotic DNA is much larger and occurs in linear strands (chromosomes) with lots of associated protein . It replicates at several simultaneous sites (more on this later). To segregate into two regions, the DNA is so large that it must first ³condense² during a process known as mitosis.

C.      Medical importance of understanding the eukaryotic cell cycle:

1.       What causes cancer? How can we prevent and cure cancer?

2.      How can we make wounds heal faster?

3.      Can we induce damaged body parts to regenerate?

4.      Can we induce undifferentiated cells to divide into organ specific cells? (e.g. stem cell research).

 

II.           The eukaryotic cell cycle involves the events of completely reproducing a eukaryotic cell.

 

A.      Interphase is all of the cycle except mitosis. The chromosomes are disperse in the cell during interphase.

B.      Mitosis is the condensation and separation of the DNA. It is associated with four events: prophase, metaphase, anaphase, and telophase.

C.      Cell division involves the separation of the chromosomes (mitosis) plus the actual dividing of the cells (cytokinesis). Cytokinesis actually usually overlaps with mitosis.

III.         More on interphase:

A.      G1 (gap1)

1.      If the cell is designed to do something other than divide, this is the time it would usually do such functions.

2.      This is the most variable of all of the stages in terms of time. It can last from minutes to years depending upon the cell type and the conditions.

3.      Some cells, such as nerve cells and muscle cells never leave G1.

4.      Cells that stay in G1 are said to stay at the R point (restriction).

5.      Why is it important to know what triggers a cell to leave G1 and enter DNA replication (S)? Most cells have strong control over this step so that they divide when they are supposed to, and do not divide when they are not.

a)       Cancer is a situation where this control is lost and cell division occurs continually. The cell does not stop in G1 when it should.

b)       Organ regeneration is not uncommon in a lot of organisms where, when an organ is lost, cells again start dividing to make a new organ. If we could control the G1 to S phase, we may be able to regenerate new arms or surgically removed livers.

c)       Nerves and muscles normally can not be replicated in vivo or in situ (because they are stuck in G1). It would be valuable to induce new nerve and muscle cells to grow. Some recent progress has been made in this area.

d)       It is simply an important part of the living process that we are curious to understand.

6.      What triggers a cell to leave G1 and enter DNA replication (S)? Cell size? Cyclic nucleotides? pH? histones doing something funny? All of these things have been implicated, but the exact answer is yet unknown. However we have learned some detail about some of the middle parts of the biochemistry of this process:

a)       Cyclin dependent kinase (CdK) must bind with cyclin (a protein) for this enzyme to be activated. The activation of this enzyme is critical in moving a cell form G1 to S.

(1)          ( a kinase is an enzyme that removes a phosphate from ATP and adds it to another molecule. Kinase reactions are very often controlling reactions that turn things on and off).

X + ATP -> XP +ADP

(2)          Some cancers have been found to have problems with CdK or cyclins.

(3)          There are actually many forms of Cdk¹s and cyclins that each play their specific roles.

b)       p53 is a protein known to inhibit Cdk¹s and thus preventing (controlling) cell division. Over half of all human cancers have defective p53.

c)       Growth factors (e.g. interlukins) can stimulate cell growth.

d)       Many cells experience contact inhibition, the situation where the cell stops dividing when it comes in contact with other cells. Cancer cells usually lose their contact inhibition ability.

B.      S (synthesis) DNA duplicates.

1.      DNA replication (detail on this later).

2.      The histones will also be duplicated during the S phase.

3.      Centrioles, if present, duplicate (sort of).

C.      G2 (gap2).

1.      Once S occurs, then G2 and mitosis seem to be obligated to occur.

2.      During this stage there are no obvious changes (microscopically) happening in the nucleus.

3.      But, obviously, there must be biochemical changes going on in preparation for mitosis.

4.      Duplication of the centrioles is usually completed.

IV.         Mitosis -  the segregation of the duplicated DNA molecules into two new nuclei. Although the process is quite continuous, it is often broken down into stages. Again note that we are talking only about eukaryotes. Prokaryotes do not do this DNA condensation. The time required for mitosis ranges from 10 min. to 3 hours.

A.      Prophase

1.      During this phase each long DNA molecule becomes highly infolded into itself in a highly defined way; a process called condensation. This apparently is important in untangling and separating the subsequent chromosomes.

a)       They become so bunched that we can visually see each individual DNA molecule in a light microscope!

b)       In interphase, eukaryotic DNA is already wrapped around histones forming nucleosomes. During prophase, this nucleosome DNA will further fold upon itself; presumably the histones are intimately involved in this process of condensation.

c)       Such a condensed strand of DNA is known as a chromosome. Since a chromosome at this stage is made up of two replicated DNA molecules stuck together, then each DNA molecule is referred to as a chromatid. Chromatin