P53: The Key to Sunbathing (The Regulation of MSH)

Introduction to P53

This essay discusses the effects of P53, its relation to sunbathing and the tanning response.

Additionally, we will be discussing the P53’s relation to cancer and its prognostic factor and

the role of MSH.

Fig 1.
The Structure of P53 (Splettstoesser)

P53 (TP 53) is a tumor suppressor gene that is considered one of the most frequent targets

for gene alterations relating to cancer. (Moshe Oren et al, 2007) It codes for a protein that

regulates the cell cycle, functioning as a tumor suppressor. In 1993 P53 was voted molecule

of the year by science magazine, and has been described as “the guardian of the genome”,

relating to ability to prevent genome mutation.

In over half of human tumors we can see the inactivation of P53. Due to many experiments

on the biochemistry an physiology of P53 relating to its cancer role, it is now appreciated

that its main role is to prevent the emergence of cells with permanently defective genomes,

which are very likely to lead to cancer.

In normal cells, P53 protein is low, but after DNA damage or other stress such as UV

radiation, a trigger response may occur, increasing the number of P53 proteins in the cell.

These proteins have three major functions: apoptosis (cell death), DNA repair and growth

arrest – stopping the cell cycle and therefore preventing replication of damaged DNA.

Apoptosis would be a final result to prevent replication of damaged DNA and avoiding

tumor growth. Although high levels of P53 can be considered a good thing when referred to

cancer suppression, too much can result in accelerated aging which will be discussed further

as an effect of excessive UV radiation.

Role of P-53 and relation to MSH

P53 is a tumour suppressor gene and is located on the seventeenth (17p13) chromosome. It

is one of the most frequent targets for genetic alteration in cancer. A lot of human tumours

are able to mutationally inactivate p53, removing its role as a tumour suppressor and

preventing the emergence of cells with permanently defective genomes, which can often

cause cancer. P53’s ability is largely due to it being able to act as a sequence special c

transcriptional regulator. (Moshe Oren et al, 2007)

It is also a key regulator of cellular responses to geno-toxic stress, and it is stabilised and

activated after DNA damage. The rapid activation of p53 by ionising radiation mostly

dependents on the ATM kinase. P53 is phosphorylated by ATM shortly after DNA damage,

resulting in enhanced stability and activity of p53.

The Mdm2 oncoprotein is a major negative regulator of P53, triggering its degradation by

ubiquitin system. In response to ionising radiation and radio-mimetic drugs, Mdm2

undergoes rapid ATM-dependent phosphorylation before to p53 accumulation. This

decreases its reactivity with the 2A10 monoclonal antibody. Phage display analysis is a

laboratory technique, for the study of proteins and protein-DNA that use bacteriophages to

connect proteins with the genetic information. From this analysis a consensus 2A10

recognition sequence was identified, possessing the core design DYS. Unexpectedly, this

design appears twice within the human Mdm2 molecule, at positions corresponding to

residues 258–260 and 393–395. Serine 395, residing within the carboxy-terminal 2A10

epitope, is the major target on Mdm2 for phosphorylation by ATM in vitro. (Ruth Maya et al,

2001)

Alpha-Msh is a a-melanocyte- stimulating hormone secreted by keratinocytes. Alpha-MSH

and other bioactive peptides are products of pro-opiomelanocortin (POMC). There is

biochemical and genetic evidence demonstrating that UV induction of POMC/MSH in skin is

directly controlled by p53. Whereas p53 potently stimulates the POMC promoter in

response to UV, the absence of p53 is associated with absence of the UV-tanning response.

The same pathway produces b-endorphin, another POMC derivative, which can contributes

to sun-seeking behavior. Furthermore, several instances of UV-independent pathologic

pigmentation are shown to involve p53 ‘‘mimicking’’ the tanning response. Therefore p53

functions as a sensor/effector for UV pigmentation, which is an everyday

environmental exposure. This pathway is activated in numerous conditions of

pathologic pigmentation and mimics the tanning response. (Rutao Cui et al. 2007)