Thursday, August 4, 2011

Protein 53 or tumor protein 53 (p53)


Protein 53 or tumor protein 53 (p53)


Introduction
p53 (also known as protein 53 or tumor protein 53), is a transcription factor that in humans is encoded by the TP53 gene.  p53 is important in multicellular organisms, where it regulates the cell cycle and thus functions as a tumor suppressor that is involved in preventing cancer. As such, p53 has been described as "the guardian of the genome," "the guardian angel gene," and the "master watchman," referring to its role in conserving stability by preventing genome mutation.

An outline of possible p53 actions with normal and damaged cells
p53 was identified in 1979 by Lionel Crawford, David P. Lane, Arnold Levine, and Lloyd Old. It had been hypothesized to exist before as the target of the SV40 virus, a strain that induced development of tumors. The TP53 gene from the mouse was first cloned by Peter Chumakov of the Russian Academy of Sciences in 1982, and independently in 1983 by Moshe Oren (Weizmann Institute). The human TP53 gene was cloned in 1984.
It was initially presumed to be an oncogene due to the use of mutated cDNA following purification of tumor cell mRNA. Its character as a tumor suppressor gene was finally revealed in 1989 by Bert Vogelstein working at Johns Hopkins School of Medicine.
The name p53 is in reference to its apparent molecular mass: it runs as a 53 kilodalton (kDa) protein on SDS-PAGE. But based on calculations from its amino acid residues, p53's mass is actually only 43.7kDa. This difference is due to the high number of proline residues in the protein which slow its migration on SDS-PAGE, thus making it appear heavier than it actually is. This effect is observed with p53 from a variety of species, including humans, rodents, frogs, and fish.

Nomenclature

p53 is also known as:

  • UniProt name: Cellular tumor antigen p53
  • Antigen NY-CO-13
  • Phosphoprotein p53
  • Transformation-related protein 53 (TRP53)
  • Tumor suppressor p53

Structure

Human p53 is a nuclear phosphoprotein of MW 53 kDa, encoded by a 20-Kb gene containing 11 exons and 10 introns, which is located on the small arm of chromosome 17. 
This gene belongs to a highly conserved gene family containing at least two other members, p63 and p73. Although these proteins are structurally and functionally related to each other, p53 seems to have evolved in higher organisms to prevent tumor development, whereas p63 and p73 have clear roles in normal developmental biology
Wild-type p53 protein contains 393 amino acids and is composed of several structural and functional domains (as shown in figure):


Figure: Schematic representation of the p53 structure. p53 contains 393 amino acids, consisting of three functional domains, i.e. an Nterminal activation domain, DNA binding domain and C-terminal tetramerization domain. The N-terminal domain includes transactivation subdomain and a PXXP region that is a proline-rich fragment. The central DNA binding domain is required for sequence-specific DNA binding and amino acid residues within this domain are frequently mutated in human cancer cells and tumor tissues. The Arg175, Gly245, Arg248, Arg249, Arg273, and Arg282 are reported to be mutation hot spots in various human cancers. The C-terminal region is considered to perform a regulatory function. Residues on this basic C-terminal domain undergo posttranslational modifications including phosphorylation and acetylation.

 NLS, nuclear localization signal sequence; NES, nuclear export signal sequence.



v  An N-terminus containing an amino-terminal domain (residues 1-42)

v  A proline-rich region with multiple copies of the PXXP sequence (residues 61-94, where X is any amino acid),

v  A central core domain (residues 102-292),

v  A C terminal region (residues 301-393) containing an oligomerization domain (residues 324-355),

v  A strongly basic carboxyl terminal regulatory domain (residues 363-393), a nuclear localization signal sequence and 3 nuclear export signal sequence.

v  The amino-terminal domain is required for transactivation activity and interacts with various transcription factors including acetyltransferases and MDM2 (murine double minute 2, which in humans is identified as Hdm2).

v  The proline-rich region plays a role in p53 stability regulated by MDM2, wherein p53 becomes more susceptible to degradation by MDM2 if this region is deleted. The central core of this protein is made up primarily of the DNA-binding domain required for sequence-specific DNA binding (the consensus sequence contains two copies of the 10-bp motif 5’-PuPuPuC(A/T)-(T/A)GPyPyPy-3’, separated by 0-13 bp).

v  The basic C-terminus of p53 also functions as a negative regulatory domain,and has also been implicated in induction of cell death. According to the allosteric model, in which C-terminal tail of p53 was considered as a negative regulator and may regulate the ability of its core DNA binding domain to lock the DNA binding domain as a latent conformation.

v  Structural studies of p53 have revealed that the majority of p53 mutations found in cancers are missense mutations that are mostly located in the central DNA-binding domain, and more than 80% of p53 mutation studies have focused on residues between 126–306.
v  In the p53 family, both p73 and p63 show considerable homology with p53 and have similar domain structures including an oligomerization domain, with over 60% amino acid identity within the DNA binding region, and all three of these proteins can induce apoptosis. However, at the same time there are many structural and functional differences between p53 and its other two family members.

Function

In its anti-cancer role, p53 works through several mechanisms:

  • It can activate DNA repair proteins when DNA has sustained damage.
  • It can induce growth arrest by holding the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.)
  • It can initiate apoptosis, the programmed cell death, if the DNA damage proves to be irreparable.
·         p53 is essential for preventing inappropriate cell proliferation and maintaining genome integrity.
·         p53 activation involves an increase in overall p53 protein level as well as qualitative changes in the protein through extensive posttranslational modification, thus resulting in activation of p53-targeted genes.
·         Many of the multiple functions of p53 including the primary role of p53 in tumor suppression, can be attributed to its ability to act as a sequence-specific transcription factor which regulates expression of different cellular genes to modulate various cellular processes, although protein-protein interactions may also play a role. In response to various types of stress, p53 is accumulated in the nucleus and binds to specific sites in the regulatory regions of p53- responsive genes, and then strongly promotes the transcription of such genes.
·          The functions of p53 target genes are diverse, corresponding to p53’s activity as a multifunctional protein.

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