Debunking myths on genetics and DNA

Thursday, October 27, 2011

P53, the anti-cancer sentinel

In my post The Missing Heritability, I hinted at what I called "protective mutations." We know that people with "risk alleles" have a higher probability of developing certain cancers, but what about people who do have those alleles and never end up developing the cancer? Do they carry "protective alleles" that counter-effect the negative risk carried by the deleterious alleles?

An astute reader (thanks!) pointed me to the tumor-suppressant protein p53. I dug up the literature on this, and it is indeed a fantastic protein. It regulates the cell cycle and, by controlling the expression of many important genes, it activates proteins that have the ability to repair DNA when it's damaged by stress factors -- damage that may otherwise lead to cancer cells. When the damage isn't "fixable," p53 initiates cell death (apoptosis) and destroys the cell. P53 is also beneficial when it comes to viral infections, as it's been shown to inhibit viral replication in human papillomavirus infections [1].

What's the link between cancer and p53?

As Vogelstein and Kinzler state in this paper, cancer is a genetic disease that originates through the accumulation of "alterations in three types of genes responsible for tumorigenesis: oncogenes, tumor-suppressor genes and stability genes." In light of its role in regulating the cell life cycle (repairing damaged DNA and initiating apoptosis), p53 is indeed a tumor-suppressant protein. And in fact, mutations in the TP53 gene, the gene that codes p53, have been found in about 50% of all cancers [2], again indicating that a healthy p53 has the ability to keep our cells "in check," whereas, on the other hand, mutations in the TP53 gene can have disastrous effects.

Because of its multiple functions, p53 orchestrates many different proteins. So, it shouldn't come as a surprise that other genes have been linked to p53 in certain cancers and, interestingly, they have the ability to partially restore the p53 tumor-suppressing function. Rather than "protective alleles" (as I had originally hypothesized), these are genes that act in tandem with p53 and are found to be either mutated or under-expressed in cancer cell lines. By restoring them, researchers were able to restore the healthy functioning of p53 as well and observe a reduction in cancer cell proliferation. These findings point to possible cancer treatment strategies aimed at restoring the normal expression of cancer-suppressant genes.

This is what I found in the literature:

Hu et al. [3] found that the protein ZNF668 has the ability to suppress breast cancer cells by regulating the stability and activity of p53. They tested this both in vitro and in mouse models. They also showed that the ability to inhibit cell proliferation was impaired in two cancer-derived ZNF668 mutant genes. The authors conclude, "our studies identify ZNF668 as a novel breast tumor suppressor gene that functions in regulating p53 stability."

Similar results have been found when researchers investigated the interaction between the protein ANKRD11 and p53, again in breast cancer [4, 5]. The presence of p53 mutations and loss of expression of ANKRD11 is associated with poor breast cancer prognosis, and the mutant p53 is less effective in regulating cellular growth and apoptosis. The researchers found that ANKRD11 expression was downregulated in breast cancer cell lines [4]: they analyzed six breast cancer cell lines and found an 89% average reduction in gene expression (P<0.01) with respect to non-malignant breast cells. On the other hand, restoration of ANKRD11 expression suppressed the growth characteristics of breast cancer cell lines, for an average reduction in proliferation of 36% after 72 hours.

What about the effects of ANKRD11 on the mutated p53 protein in these cancer cells?

The authors found that ANKRD11 was able suppress the oncogenic properties of the mutant p53, and, furthermore, it had the ability to restore p53 functions by reverting it to its wild-type (non-mutant) conformation [5]. In order to see this, they used an antibody that binds to the "healthy" p53 and showed enhanced binding in the presence of the protein ANKRD11, thus proving the reversion from the mutant p53 to the wild-type one.

In conclusion, p53 is indeed a great sentinel that keeps us cancer-free, but when things go wrong, other genes can be targeted to try and revert the effect of deleterious mutations. Something to keep an eye on for future cancer treatments!

[1] Brown, C., Kowalczyk, A., Taylor, E., Morgan, I., & Gaston, K. (2008). p53 represses human papillomavirus type 16 DNA replication via the viral E2 protein Virology Journal, 5 (1) DOI: 10.1186/1743-422X-5-5

[2] Hollstein M, Sidransky D, Vogelstein B, & Harris CC (1991). p53 mutations in human cancers. Science (New York, N.Y.), 253 (5015), 49-53 PMID: 1905840

[3] Hu R, Peng G, Dai H, Breuer EK, Stemke-Hale K, Li K, Gonzalez-Angulo AM, Mills GB, & Lin SY (2011). ZNF668 Functions as a Tumor Suppressor by Regulating p53 Stability and Function in Breast Cancer. Cancer research, 71 (20), 6524-34 PMID: 21852383

[4] Neilsen PM, Cheney KM, Li CW, Chen JD, Cawrse JE, Schulz RB, Powell JA, Kumar R, & Callen DF (2008). Identification of ANKRD11 as a p53 coactivator. Journal of cell science, 121 (Pt 21), 3541-52 PMID: 18840648

[5] Noll JE, Jeffery J, Al-Ejeh F, Kumar R, Khanna KK, Callen DF, & Neilsen PM (2011). Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11. Oncogene PMID: 21986947

Photo: clay jar hand-made by my wonderful friend Rosi. Focal length 85mm, shutter speed 1/10, f-stop 5.6.


  1. Ooo. Astute. I like it.

    Tumor suppressors are pretty awesome. I know p53 has been a drug target for awhile but I think the cancer expert consensus in on targeting the modulators of p53. Mostly because it acts as a central hub for signal transduction pathways. There are a lot of ways direct treatment can go wrong. That's always the trouble with cancer treatments. How to kill the bad without screwing up the good?

  2. Thanks, my astute reader! :)

    And yes, you're absolutely right. That's also the problem with cancer vaccines, because tumor cells can be flagged as sick cells but they are also "self" and the immune system knows not to attack "self"... Things are quite delicate and can easily go wrong.

    It's a very challenging conundrum.

  3. out of curiousity, i researched about cancer and i found that some of its signs are found under chronic disease.

    as said in wikipedia,

    "A chronic disease is a disease or other human health condition that is persistent or long-lasting in nature.[1] The term chronic is usually applied when the course of the disease lasts for more than three months. Common chronic diseases include asthma, cancer, diabetes and HIV/AIDS."

    and I also managed to researched a site regarding "5 Signs You Might Have a Chronic Disease" you can find it here ( which also talks about Chronic disease. this is very worrying.


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