הפניתי את שאלתכם לפרופ' שיפמן, החוקר המוביל בעולם בחקר של פילים. להלן תשובתו לשאלותיכם הכוללת גם את השאלות המתורגמות לאנגלית:
Dear Eilam and Ela,
Thank you for your questions to Dr. Moshe Oren. Let me try to answer (in English) your questions below. We have been studying elephants and their remarkable cancer resistance due to additional p53 copies for almost 7 years now. It is quite a fascinating area of science!
Is the reduced cancer frequency in elephants due to excessive p53 activity, or are there additional unique mechanisms in elephants that contribute to the reduced cancer frequency?
We believe there are several different ways that the elephants have naturally reduced their cancer risk. Our laboratory at Huntsman Cancer Institute at the University of Utah (located in Salt Lake City, Utah, United States) believes that the extra copies of p53 in elephants is probably one of the strongest ways that cancer is avoided. We have been studying all of the different versions of p53 to try to unlock their secrets to natural cancer resistance. However, we also recognize that additional genes may be playing a role in stopping cancer from developing in elephants and that these protective mechanisms also evolved over 55 million years of elephant evolution. Please see below for some videos and press releases related to elephant cancer resistance, both by p53 and other mechanisms.
Is the tendency for apoptosis in elephants due to enhanced p53 activity? If so, is this because all paralogous p53 genes are expressed and thus there is more p53 in the cells, or is it because the various paralogues are different from each other and some have higher activity than the primordial gene, or they possess different complementary activities?
These are excellent questions! Thus far, our data supports that elephant p53 (EP53) works “better” than human p53 at triggering a more robust apoptotic response. You can think of this as “enhanced activity.” One of the 20 versions of EP53 that most closely resembles human p53 we call EP53-ancestral --- because it is the one that looks like the same TP53 gene in all animals throughout evolutionary time. It’s about 80% similar. EP53-ancestral causes more apoptosis than human p53 when you do the experiments with human vs. elephant p53 by itself. The other 19 versions of EP53 we call EP53-retrogenes --- because these were re-inserted throughout evolutionary time and actually went from DNA -> RNA -> back to DNA. These are called “retrogenes” or “pseudogenes.” However, they still work together with EP53-ancestral to produce the increased apoptosis that we see in elephant cells. There are complementary activities when both the EP53-anc and the EP53-retrogenes come together in a cell. Remember that there is 1 version of EP53-ancestral (2 copies) and 19 different versions of EP53-retrogenes (18 copies). That means the elephants have 40 copies of p53 vs. only 2 copies in humans. We think this is true in all types of elephants.
Is the accelerated apoptotic response in elephants due to the “resurrection” of the LIF6 pseudogene which leads to faster apoptosis, or is this due to the fact that a lower threshold of DNA damage is sufficient for induction of apoptosis by p53?
This work on LIF6 pseudogene was done by a different researcher and has not yet been replicated in the scientific literature. The answer to this question about LIF6 leading to faster apoptosis is still being explored, including its interaction with p53.
Have p53 gene sequences been determined in other mammals of large body mass, such as whales? Has a correlation been found between the number of p53 gene copies and gene frequency in large mammals (such as whales)?
Other mammals with large body mass, such as whales, do not have extra copies of p53 like the elephant. However, there have been some modifications to the sequence of the DNA in these other mammalian p53 genes and this may contribute to their cancer resistance. More likely, though, there have been other mechanisms besides p53 amplification that are contributing to increased cancer resistance. Most animals only have 1 version (2 copies) of p53 like humans, although a handful have more like the cancer resistant Little Brown Bat.
Why have the p53 retrogenes evolved in elephants and not in the genomes of other animals? How has the retrotransposition process occurred in elephant cells? Is this because the process of gene retrotransposition is more frequent in elephants?
Evolution is stochastic (random), and so we think that in elephants, 55 million years ago, there was p53 retrotransposition that led to survival advantage due to decreased cancer rates. This was selected throughout evolutionary time. We don’t think there is anything special about elephant genomes that led to more p53 and retrotransposition events. The elephants were just “lucky” that it occurred so long ago and that this gave them such a wonderful results in terms of cancer protection. Now, it is our goal to continue to study this beautiful event in evolution to try to create a world with more elephants in the wild and less cancer in people!