Stem Cells, Vol. 17, No. 3, 189-190,
May 1999
© 1999 AlphaMed Press
The Molecular Perspective: p53 Tumor Suppressor
David S. Goodsell
The Scripps Research Institute, Department of Molecular Biology, La Jolla, California, USA
Dr. David S. Goodsell, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
The p53 tumor suppressor has been termed "the Guardian of the Cell." It is not essential for life—mice that are deficient in this protein are born seemingly normal—but it is essential in its role of protecting an organism from rogue cells. p53 guards two gates: a gate to life and a gate to death. Sensing damage to DNA, p53 can initiate two processes to isolate the damaged cell and prevent its uncontrolled growth. It can halt cell division, freezing the cell at the G1 checkpoint of the cellular cycle. The cell is unable to reproduce, and its damaged genome is safely isolated. p53 can also initiate a more permanent solution: programmed cell death, or apoptosis.
p53 tumor suppressor acts as transcriptional activator, controlling the expression of a variety of genes important in cell cycle regulation and apoptosis. p53, composed of four identical subunits, binds to a specific site on the DNA, and interacts with transcription interaction factors, leading to the initiation of transcription by RNA polymerase II. p53 itself is present at extremely low levels in most cells, and has a life span of mere minutes. These low levels allow the action of p53 to be genetically controlled. Levels may be raised quickly by synthesis of more p53, and high levels are quickly reduced when synthesis abates. The induction of p53 has a hair-trigger: even a single double-stranded break of the DNA has been predicted to be enough.
As one might expect, disruption of a process with such an important function will have dire consequences. Approximately half of all cases of human cancer may be attributed to a defective p53 protein. Most of these are caused by missense mutations in the p53 gene, changing one amino acid in the protein to another. This may alter the binding of the protein to DNA or to the transcription factors, corrupting the signal from p53 to the cellular machinery, or it may unnaturally increase the stability of the protein, corrupting the delicate balance of synthesis and degradation that controls the level of p53 in the cell. Either way, p53 is unable to open the gates to cell cycle arrest or apoptosis, and cancerous cells are allowed to proliferate without control.
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Additional Reading:
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 Additional Reading:
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- Ko LJ, Prives C. p53: puzzle and paradigm. Genes Dev 1996;10:1054-1072.
- Gottlieb TM, Oren M. p53 in growth control and neoplasia. Biochim Biophys Acta 1996;1287:77-102.
- Cho Y, Gorina S, Jeffrey PD et al. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 1994;265:346-355.
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p53 tumor suppressor. For those who think of proteins as uniformly compact and globular, the structure of p53 will come as a surprise. It is composed of four identical chains, bound together to form a flexible, four-armed starfish. Each chain folds into three structured domains, connected by long, flexible linkers. At the tip of each arm is an activation domain, which binds to the transcriptional machinery and activates gene expression. This domain also binds to the regulatory protein MDM2. At the center of each arm is the largest domain, the globular DNA-binding domain that binds specifically to the target DNA site. These DNA-binding domains are the sites of most of the cancer-causing mutations observed in p53. At the center of the tetramer, the four chains interlock, forming a strong Celtic knot that ties the molecule together.
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p53 tumor suppressor in action. Gene expression is controlled by a complex web of protein interactions. The process is shown here along the yellow DNA strand running from top to bottom through the center of the picture. p53 tumor suppressor, shown here in red, binds to a specific site on the DNA, and activates transcription by binding to transcription factors. Here, one of the p53 activation domains is shown bound to TATA-binding protein and TFIID, both together shown as a small blue-green complex bound to the DNA below p53. RNA polymerase II, shown in blue, with the help of a host of other transcriptional activation proteins, shown as the large blue-green crescent-shaped molecule, then recognizes the complex, and begins transcribing the DNA into RNA. In the picture, two RNA polymerase molecules have begun their journey down the DNA strand, gradually constructing their new RNA strands, shown in white.
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