Re: How does p53 mutate?

	This is a very good question! (but, also a complicated one!)  First, do 
you know what "p53" stands for?  It means "protein, 53 KiloDaltons (KDa) in 
size". (KiloDaltons is just a unit that biochemists use to measure the size 
of proteins)  
	Roughly 50% of all human cancer cells possess a mutation in p53.  P53 
is an important tumor SUPPRESSOR in cells.  Tumor suppressors are special 
proteins that inhibit cells from growing and dividing uncontrollably and 
causing cancer.  p53 works in numerous ways to inhibit cell division 
(mitosis) within the cell, by inhibiting the progression of the cell cycle, 
DNA replication and at times, activating a cell-suicide mechanism called 
Apoptosis or "programmed cell death".  Mutations in p53 that are found in 
cancer cells, therefore, usually make p53 nonfunctional (unable to perform 
tumor suppressor functions) or the mutations make p53 unstable (when 
proteins are unstable they break down easily and are degraded).
	So, how does p53 perform all these different tumor suppressor 
activities? When normal (not mutated) p53 is ACTIVATED (by phosphorylation 
from other proteins called kinases), it now is able to increase 
transcription (make mRNA for protein synthesis) of cell division INHIBITORS. 
Proteins like p53 that regulate transcription of genes in the nucleus are 
called TRANSCRIPTION FACTORS.  Some of the cell division inhibitors can 
inhibit the beginning of the cell cycle called the "G1" phase.  The G1 
(Growth 1) phase is the time during which cells are preparing for DNA 
Replication or DNA synthesis (the "S" phase).  (Remember before Mitosis, the 
fist thing that a cell must do before it divides is make another copy of its 
DNA)  So, one of the cell cycle inhibitors that p53 increases transcription 
of is called p21.  
	Another way that p53 inhibits cell division is by increasing the 
transcription of genes that directly inhibit machinery required for DNA 
replication.  DNA replication is a big task for the cell, and many proteins 
are required to make sure the replication is done completely and correctly.
p53 inhibits replication by helping transcribe a gene that directly inhibits 
a protein required for replication called PCDNA.
	Finally, p53 can help transcribe a gene that activates APOPTOSIS 
(programmed cell death). This is a very complicated mechanism the cell has 
to "kill itself" when things are going wrong.  For example, if a cancer cell 
is dividing uncontrollably, the cell has apoptosis to kill it before it does 
any damage to the organism.  
	Now that you know what p53 is supposed to do in the cell, you can now 
imagine how different mutations in it could lead to big problems- like 
cancer.  If you have a mutation in p53 that makes it unable to activate the 
transcription of the cell cycle inhibitors (like p21)- the cell might 
continue dividing and grow into a tumor.  Or, if you have a mutation p53 
ability to be activated by the kinases, then p53 will never be able to act 
as transcription factor for any genes.  
	I hope this helps you! It is complicated and there may be terms that 
you don't understand, but I encourage you to look into Cell Biology books 
(not just Biology) in your library.
	Good Luck!
	Elena Rodriguez
	2nd year Graduate Student
	University of California, Berkeley