p53 Signaling Pathway

Tumor protein p53 (TP53) is a gene that codes for a protein that regulates the cell cycle and tumor suppression.  The p53 gene name comes from the molecular mass of this protein, which is 53 kilodaltons.   This gene is found on chromosome 17. The signaling pathway in which p53 exists is extremely important in the suppression of cancer and prevention of genome mutation.

History of p53

This protein was isolated in 1979 by David Lane, Arnold Levine, and William Old.  P53 was discovered to be a tumor suppressor gene in 1989.  Once it turned out that this gene was actually a proponent for the fight against cancer, research into this pathway became a very high priority.  The p53 pathway is one of the most critical pathways in the fight against cancer.

What does p53 do

When the cell is at homeostasis, the protein is at low levels. It has a negative regulator called Mdm2.  This protein represses p53 protein levels in the body.  With p53 activation, the pathway will cause cell cycle cessation, which allows repair and cell survival.  It can be activated by telomere shortening, metabolic stress, viral infection, ribosomal stress, and oxidative stress. It may also cause the cell to go through cell death, known as apoptosis.  If p53 is defective, it can allow for abnormal cell growth and possibly cancer.   The main function of p53 involves growth arrest, DNA repair, and apoptosis.

Growth Arrest – The cell cycle is broken into growth phases and a synthesis phase, which are part of the interphase of the cell cycle.  The mitotic phase is when the duplicated DNA is split into two cells.  If the cell is not working properly or the DNA is mutated it may trigger the p53 pathway, which will cause growth arrest.  P53 needs its cofactor, p21, to help with cell cycle arrest.  Other genes in this pathway that are involved in growth arrest are Cdc25C, BTG2, and B99.  This cell cycle arrest prevents cancerous or mutant cells from dividing and causing growth and triggering cancer.

DNA Repair – Most DNA damage is removed and the removed region is then resynthesized to make for healthy DNA.  There are many types of DNA damage and several repair systems in the body that can help with restore this damage.  UV light is one major cause of damage to DNA, along with gamma irradiation, and heat/cold shock.  Some genes in the p53 pathway that are involved in DNA repair include, GADD45, XPC, p48XPE, and p53R2.

Apoptosis – If the cell is too damaged and repair is not possible, it may cause the apoptosis pathway to activate.  This pathway is also known as the cell death program pathway.  This cell death pathway causes the cell to break down into tiny fragments and it signals for phagocytic (debris-eating) cells to remove the fragments.  Some genes involved in this pathway are BAX Bcl2, BID, NOXA, and PUMA.  Some cells are programmed to be deleted to make a structure like a hand.  Some cells are abnormal and need to die to keep the organism alive.  Other cells are removed to make way for new cells.  A great example is the immune system, where a pathogen is recognized and the immune system cells begin to divide extensively to fight the pathogen.  Once the pathogen has been cleared, the immune system no longer needs all of the pathogen-specific cells, so they must be cleared to restore balance.  Apoptosis is necessary to keep healthy cells in the body and mutant cells out of the body.

TP53 Gene

If the TP53 gene is damaged, tumor suppression is severely reduced and cancer can be the outcome.   Carrying only one functional copy of the gene may cause tumor development in adulthood.  More than half of tumors have mutations or deletions in the TP53 genes.  

P53 Pathway

The P53 pathway is quite complex in nature.  There are 31 genes that are regulated by the activation of p53.  Some of these genes can be found in the DNA repair process, apoptosis, and growth arrest in the cell.  P53 is negatively regulated by MDM2, a ubiquitin ligase.  MDM-2 and p53 form an autoregulatory loop, where p53 synthesizes MDM-2 and p53 is ultimately degraded.  P19 ARF also binds to MDM-2 and inhibits ubiquitination of p53.   There is also the damage pathway where UV or stress signals cause DNA damage where the ATM protein kinase (CHK2) is activated and in the absence of p53 activation is delayed.  The CHK1 gene can also be activated and cause altering of the p53 response.

P53 as a Therapeutic Target

Many studies have been performed to replace defective TP53 genes with wild-type TP53 to see if it can reverse the effects of damage and help fight cancer.  Using an internal pathway that already works to naturally kill tumor cells is the ultimate fight against cancer.  The problem with p53 targeted therapy is the fact that it is a transcription factor with complicated protein-protein interactions.  It has many branches in its pathway that can be altered.  There is also the chance that some reactivation of the p-53 pathway may cause cell cycle arrest and not apoptosis as desired.  The new treatments may be more successful if the biomarkers are customized to the individual to provide individualized targets.  Many studies are trying to boost levels of p53 to help with its anti-tumor properties and adding in combination chemotherapy to fight the p53-resistant cancer cells.  This combination therapy is thought to help achieve maximal therapeutic efficacy and decrease tumor resistance.