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Sarah Pulliam
Biology 303
Dr. Bert Ely
8 November 2007
The Arf/p53 Pathway and Its Role in Cancer Suppression and Longevity
The p53 gene is the most frequently mutated gene found in human cancers. It occurs in
over 50 percent of all cancers (Cummings et al. 444). The p53 gene codes for a protein that acts
as a transcription factor, repressing or stimulating the transcription of over 50 other genes. This
is known as the p53 pathway. The p53 gene is activated by numerous stressors that indicate cell
damage. One stressor in particular that signals activation of p53 is damage to the integrity of the
DNA template (Harris and Levine 2899). The activity of the p53 protein is increased when DNA
damage is detected in a normal cell, and one of two different responses is initiated. The cell
cycle is stopped temporarily and the DNA is repaired, or, if the DNA cannot be repaired, then
cell apoptosis (cell death) and cell senescence are induced. Multiple checkpoints exist
throughout the cell cycle. At any of these points, the p53 gene can initiate cell arrest or apoptosis
(Cummings et al. 445). Complicated positive and negative feedback loops are involved in each
of these circumstances (Harris and Levine 2899). In cancer cells, the p53 gene often is not
functional, and cell arrest or apoptosis does not occur when cell damage is detected. This failure
allows a cell to continue unchecked through the cell cycle, causing high mutation rates that
ultimately lead to a tumor. Thus, the p53 gene is very important to genomic integrity and is
known as a potent tumor suppressor gene (Cummings et al. 444-445)
Arf is a gene locus responsible for stabilizing the p53 gene, leading to the cell growth
arrest or apoptosis that is characteristic of the p53 gene. In other words, the Arf gene aids the
p53 gene in managing DNA repair. The Arf/p53 pathway is therefore known collectively as a
tumor suppressor pathway (Blasco et al. 375). One of the main reasons the p53 gene is currently
an area or intense research is due to its known cancer resistance effects. Scientists desire to
determine the mechanisms behind this intriguing corollary.
Recent studies have focused on the effects of gene expression in the Arf/p53 pathway on
both cancer suppression and longevity. In “Delayed ageing through damage protection by the
Arf/p53 pathway,” Blasco et al. studied the relationship between over expression of both Arf and
p53 genes in the pathway and the subsequent relationship between cancer resistance and
longevity in mice. Four different mouse models are genetically engineered for the experiment:
control (wild type) mice, mice with a single extra gene-dose of either Arf (s-Arf) or p53 (s-p53),
and mice with an extra gene dose of both Arf and p53 (s-Arf/p53) (Blasco et al. 375).
The s-Arf/p53 mice with double over expression demonstrate a significant delay in aging
along with cancer resistance. Focusing on the reason for delayed senescence, Blasco et al.
discovered that decreased oxidative damage is the main mechanism behind this anti-aging affect.
Reactive oxygen species (ROS) were generated at a much lower rate in the doubly overexpressed mice. The lower ROS production rate translates as a decrease in overall accumulation
of oxidative damage within the s-Arf/p53 mice. Intermediate levels of oxidative damage were
observed in the s-Arf mice and s-p53 mice (Blasco et al. 377-378). “These findings support the
notion that the Arf/p53 pathway confers protection against ageing-associated oxidative damage”
(Blasco et al. 377).
The protective activity of p53 against cancer is constant throughout the lifespan of the sArf/p53 mice. The antioxidant levels increased in all s-Arf/p53 mice and remained elevated in
both young and old mice. Blasco et al. concluded that the s-Arf/p53 mice live longer due to an
antioxidant affect created when both the Arf and p53 genes are over expressed at the same time.
In another study, Pinkston, et al. found the same results in Caenorhabditis elegans, a
nematode worm. Just as the mice in Blasco et al. experienced a significant increase in survival
rates and a decrease in susceptibility to cancer, the nematode worms also demonstrated a
connection between tumor suppression and increased life span related to the p53 pathway.
Diverse mutations that increase longevity also increase cancer resistance through activation of
p53 in C. elegans (Pinkston et al. 971-972). This suggests that similar genes present in both
mice and nematode worms affect cancer and longevity simultaneously.
In many different species, cancer suppression and longevity have been recorded as
undergoing co-evolution (Blasco et al. 375). These two studies show evidence to support this
theory. Both mice and C. elegans display a correlation between longevity and tumor resistance.
Not all studies have found a connection between over expression of p53 and increased
longevity. A study by Tyner, et al. created mice that express a truncated form of the p53 gene
that contains a defective (partly deleted) p53 allele, delineated as the “m” allele. These mice are
highly resistant to tumors; however, they also have shortened lifespans and show signs of early
aging phenotypes. Some examples of such phenotypes are weight loss, hunched spines, lethargy,
osteoporosis, and hair thinning. Tyner et al. concludes that the presence of the m allele, when
combined with wild-type p53, augments p53 protein stability, thus increasing the protein’s
effectiveness against DNA damage and preventing tumor formation. At the same time, this
allele creates a 23% reduction in the median lifespan of the mice. The scientists were unable to
determine the reason for pre-mature aging. They propose that enhanced activity of wild-type
p53 in some tissues of the mice cause early aging phenotypes (Tyner et al. 45-53). Such a
hypothesis, however, somewhat contradicts the conclusions of Blasco et al. It is possible that
enhanced activity of the p53 gene alone leads to accelerated aging, while over expression of both
the Arf and p53 genes combined negate any early aging affects, ultimately causing an increase in
longevity and tumor suppression.
The murine double-minute gene 2 (Mdm2) is a powerful inhibitor of p53. Mendrysa et
al. generated mice with different levels of deficiency in Mdm2, possessing constitutively high
p53 activities. The high p53 gene activity effectively suppressed the formation of tumors in all
mice with high p53 expression, and the loss of p53 in mice exacerbates the growth of tumors.
However, normal aging was observed for all types of mice. Therefore, an increase in p53 gene
activity due to deficiency in Mdm2 does not lead to pre-mature aging or increased longevity. No
adverse effects occur with Mdm2 deficiency in mice (Mendrysa et al. 17-19).
Due to its impact on cancerous growth, “activation of the p53 tumor suppressor is a
current goal in many cancer therapeutic studies” (Mendrysa et al. 17). The p53 gene pathway is
currently a topic of great importance in the scientific community. The four studies mentioned
here focus on different aspects of this gene and intriguingly obtain differing results. Increasing
gene expression through insertion of genes for both Arf and p53 leads to increased longevity and
cancer suppression in mice and C. elegans. Deleting a portion of the p53 allele also causes
elevated tumor suppression, but leads to pre-mature aging and shortened lifespans in mice.
Increasing the activity of the p53 gene by decreasing Mdm2 expression leads to increased tumor
suppression and normal aging. The implications of these findings are incredible. The over
expression of p53 could one day be applied to human cancers, effectively providing a “cure” for
cancer. Much more research needs to be conducted to gain a better understanding of the p53
gene pathway before this dream can become a reality. Complicated results develop when
meddling with genetics, and we do not yet know all of the reasons behind the recorded results.
Even so, this research provides hope for the future and further insight into the workings of
genetics. This is one more example of how our genes could be the answer to one of the most
deadly diseases affecting mankind today.
Works Cited
Blasco, Maria A. et al. “Delayed ageing through damage protection by the Arf/p53 pathway.”
Nature 448 (2007): 375-379.
Cummings, Michael R., Klug, William S., and Charlotte A. Spencer. Concepts of Genetics. New
Jersey: Pearson Education, 2006.
Harris, S. L. & Levine, A. J. “The p53 pathway: positive and negative feedback loops.”
Oncogene 24 (2005): 2899–2908.
Mendrysa, S. M. et al. “Tumor suppression and normal aging in mice with constitutively high
p53 activity.” Genes Dev. 20 (2006): 16–21.
Pinkston, J. M., Garigan, D., Hansen, M. & Kenyon, C. “Mutations that increase the life span of
C. elegans inhibit tumor growth.” Science 313 (2006): 971–975.
Tyner, S. D. et al. “p53 mutant mice that display early ageing-associated phenotypes.” Nature
415 (2002): 45–53.