p53 & microRNA

My extreme originality for a post specifically for the cancer research blog carnival resulted in me checking out the top 20 downloaded articles from one of the top cancer research journals, Cancer Cell. Number 15 at the time of posting was "p53 enters the microRNA world" (short free abstract). This one is near and dear to me.
p53, "the guardian of the genome" is a particularly intensely studied tumour suppressor protein because it has been found mutated in almost all cancer types. It is a transcription factor that regulates/coordinates important and diverse cell fate programs such as cell cycle, apoptosis (programmed cell death), DNA repair and senescence. What is new about p53 in this cell paper (review subscription required) is that another transcriptional target has been identified as the microRNA family miR-34.
MicroRNAs are small RNAs that repress translation of target mRNAs. Target mRNAs contain partially complementary sequence in their 3'untranslated regions (3'UTR). New functions, activities and mRNA targets of microRNAs are being discovered at a rapid pace as researchers try to catch up on this important mechanism of gene regulation that has been a large oversight until their relatively recent discovery.
An connection between microRNAs and p53 is that in addition to specific transcription activation of genes, p53 has also been found to inhibit expression of some genes, for instance those involved in cell cycle. Since this is the function of microRNAs perhaps this was a mechanism by which p53 can mediate some of its effects. Also it is becoming obvious that aberrant expression of microRNAs accompanies cancer phenotypes.
A barrage of papers in late 2007 showed that the miR-34 family are direct transcriptional targets of p53. So the question was if p53 has all these important cellular function how much of that can be attributed to the microRNAs transcribed by activated p53? As it turns out quite a bit. Expression of miR-34 microRNAs results in cell cycle arrest, inhibited colony formation, senescence, tumour cell senescence, and apoptosis in various studies. And based on inhibition of miR-34, it is possible to say that miR-34 may be sufficient and required for tumour suppression by p53. Also important miR-34 mRNA targets were identified as crucial genes involved in cell cycle and apoptosis.
Interestingly miR-34 loss is observed in neuroblasoma, its expression is low or undetectable in 11 of 15 pancreatic cancer cell lines, and its expression is decreased by more than 90% in 6 out of 14 lung cancers.
So in summary, perhaps the tumour suppressing function of p53 is mediated through small RNAs! Obviously p53 itself is required in the cell but these studies point to novel therapies involving restoration or ectopic expression of miR-34.

Reading through nonsense

We recently heard a solid journal club presentation about genetic nonsense mutations. Nonsense mutations are point mutations in the DNA sequence that introduce a premature stop (or nonsense) codon and can lead to a truncated protein (or, in many cases, no protein at all as nonsense codons are detected by the presence of exon-junction complexes and the mRNA is degraded). The paper discussed described a drug, PTC124, that is entering the final phase of clinical trials that supresses premature termination and allows readthrough of nonsense codons by the translational machinery and production of a full-length protein.

What does this have to do with cancer? The paper discusses the therapeutic potential of the drug in terms of cystic fibrosis and muscular dystrophy - two diseases with pathology known to be caused (at least in some cases) by nonsense mutations in specific genes; CTFR for cystic fibrosis and dystrophin for muscular dystrophy. An obvious target for cancer therapeutics is p53. The p53 gene is mutated in over 50% of human tumours and of those mutants, almost 8% are nonsense mutations (source:IARC p53 mutation database). Research has shown that reactivation of p53 has therapeutic potential in mouse models of cancer, leading to growth arrest and regression of tumours. One need not limit this idea to p53. Nonsense mutations in many other genes, such as BRCA or Rb, have been associated with cancer and bypass of nonsense-mediated decay represents an interesting area to explore when dealing with cancer, and other, therapeutics.

Bayblab podcast Episode11-part1of2

On this episode we talk about recent findings regarding p53 in aging which drastically change the balance between cancer and senescence, we talk about the implication of the reversibility of Rett syndrome and finally Bayman reports on the 3rd international conference on synthetic biology. With special musical guest Kevin Z.

Stem cells and cancer, forget everything you know

I was pretty happy with the theory of cancer being a trade off for longevity, and now this nature paper comes and changes everything. It used to be simple, we have evolved a system of balances and checkpoints, which prevents stem cells from growing uncontrollably and turning into cancer as a result of induced or spontaneous mutations. This balance creates a condition where the stronger the system is, the more stem cells get purged and longevity is diminished to the benefit of being cancer free. Conversely a balance which tolerates more errors, has the benefit of conferring longer longevity to the detriment of getting cancer. It was so nice and simple. All the experiments so far such as overexpressing p53 agreed with that hypothesis. But now this team in Spain show that if you add an additional copy of p53, within its natural promoter, you get to have your cake and eat it too, longer longevity by 16% while the animal appear more youthfull and have reduced incidence of cancer. It seems the key is to express p53 when it's appropriate... It reminds me how ras expression in some system, depending on whether it's from a strong promoter, or it's endogenous promoter, gives diametrically opposed results, senescence vs transformation...

On a somewhat related topic, a new twist to the old oct4/c-myc/sox2/flf4 induced stem cells is that if you select for nanog, you can get the formation of germ cells. The drawback is that 20% of the offspring develop tumour, most likely because of c-myc. Is the change induced by c-myc permanent? if it was expressed only transiently, could we get around this problem? Somehow I suspect not, but I've recently been obsessed with generation-skipping epigenetic effects carried in the germline (hopefully more on this subject later...).

Bugs in PLOS ONE

PLoS ONE is the sujet du jour in the bay today. The quality of the submissions in PLoS has been increasing, but how long will that last? We had a journal club concerning a new report in PLoS about P53 mutations in ovarian cancer suggesting that patients with mutated p53 actually respond better to chemotherapy, probably because they have a harder time repairing damage, but can still undergo apoptosis in a p53-independent manner. The findings are not as novel as they might sound since it's been known for a while that in some instances, the oh-so-famous p53 tumour supressor can misbehave. P53 loss of function renders cells suceptible to DNA dammage and p53-mediated senescence of stromal cells may be required for the initiation of certain types of tumour. At the end of the talk, some of the PIs expressed their mistrust of this free-for-all that is PLoS ONE. Is this a generation gap in science? Are we just so used to the wikipedia, facebook, youtube, digg, blog sharing networks that we think science should be freed, liberated. I think if we've learned anything from the internet, it is that the masses are generally less intelligent than the individuals that they are comprised of.

Take the latest hot paper in PLoS ONE, "Order in spontaneous behavior". In that paper they hooked up fruit flies to a flight simulator, and because the fly can generate erratic patterns of flight that are endogenous to their neuronal circuitry at that instance, and not merely pre-wired, the authors concluded that they have a form of free will. Free will as the author points out, is an oxymoron: "the term ‘will’ would not apply if our actions were completely random and it would not be ‘free’ if they were entirely determined. So if there is free will, it must be somewhere between chance and necessity - which is exactly where fly behavior comes to lie."

This echoes what Einstein believed: "I don’t believe in the freedom of the will. Schopenhauer’s saying, that a human can very well do what he wants, but can not will what he wants, accompanies me in all of life’s circumstances and reconciles me with the actions of humans, even when they are truly distressing. This knowledge of the non-freedom of the will protects me from losing my good humor and taking much too seriously myself and my fellow humans as acting and judging individuals".

Which leads me to the quality of the reviewers on PLoS. Most PI's are obviously too busy to give free time to peer-review stuff on the internet that wont get them any type of recognition. Furthermore it blurs the line between "expert in the field" peer review and "random degenerate grad student" review. And really, when the best young minds are free to write anything on the internet, what comes out is probably "I for one welcome our new cyborg fruit fly overlords". What we lack is accountability and a positive reward in your career from contributing to peer-review, or publishing in non-traditional journals (is it even a journal?).

On the one hand some of the reviews appear quite adequate, yet some seem to be overly philosophical, probably because they were written from out-of-field scientists and not experts: "The findings actually have nothing to do with free will. Free will is a feeling I have (when I do something deliberately) that I am doing what I am doing because I feel like it: a feeling that my willing it is the cause of my doing it. It is undeniably true that that is what it feels like to do something deliberately. But whether what feels like the cause -- feeling -- is indeed the cause of my doing is an entirely different matter. The real cause might, for example, be a fractal order mechanism of the kind reported by Maye et al. But that mechanism is the causal mechanism it is irrespective of whether it happens to be accompanied by (or generates) feelings. And it certainly does not explain how or why we (let alone the fruit fly) feel anything at all. And without feeling there is no free will, just mechanisms, whether deterministic or nondeterministic -- unless we are ready to believe in telekinesis."

But what really took me over the edge, is this blog spamming on that paper's annotations. It's one thing for the bayblab to spam digg, but this is a taste of what's to come to the scientific discussion and peer review process if it remains open...

Vitamin D Supplementation the Answer for Cancer?

This weekend the Globe and Mail published a piece on what promise to be the blockbuster findings of a study done by researchers in Nebraska:

"A four-year clinical trial involving 1,200 women found those taking the vitamin had about a 60-per-cent reduction in cancer incidence, compared with those who didn't take it, a drop so large -- twice the impact on cancer attributed to smoking -- it almost looks like a typographical error."

The women were apparently given 1,100 IU of vitamin D3 per day over the four years.

These claims are exciting but given their grandeur must also be greeted with skepticism. I am therefore anxious to examine the data myself. Unfortunately the article failed to mention when, or in which peer-reviewed (I assume) journal these results will be published. However the article did cite one of the authors as Robert Heaney, MD, of Creighton University, who "has worked for over 45 years in the study of osteoporosis and calcium physiology, and has published more than 300 original papers, chapters, monographs, and reviews in scientific and educational fields".

Check back for updates here on the bayblab as more information becomes available.

Also, see the slashdot post for interesting discussion, including why vitamin D has nothing to do with the evolution of human skin colour.

Update: A representative from the Creighton University Medical Center has informed me that the principal author of the study is in fact Joan Lappe, PhD in Nursing and Associate Professor and Creighton.

Update 2: I have also been informed that the article will appear in the June edition of The Journal of Clinical Nutrition. However, upon my request (wherein I identified myself as a member of the cancer research community), the authors informed me that no further information will be made available until the study is published. Which leaves me scratching my head as to how the Globe and Mail got a hold of the results and chose to jump on the story when the results haven't even yet been made available to members of the scientific community for discussion and scrutiny. Interestingly, no other media outlet accessible to Google news has reported on the study to date.

Update 3: Interesting paper that Jim Wint pointed out is in fact real and recently appeared in Cell - see "Central Role of p53 in the Suntan Response and Pathologic Hyperpigmentation". Good to see even tanning bed proprietors are up on the scientific literature. I love it! (Haven't read the paper yet though, so can't say at this point whether I think it supports his claims.)

Update 4: I just bought 120, 000 IU of vitamin D3 at Shopper's Drug Mart for $6.99. Figured it couldn't hurt. Based on my previous experience with supplements, I'll take it faithfully for a couple of days then forget the whole thing.

Gene therapy for cancer : China leading the way

Move over cold FX, the new hotness in questionable approved drugs comes from China. Sibiono Genetech 's drug, Gendicine is based on a replication-deficient adenovirus delivering wt P53. So far it has proven to be quite safe in over 3500 patients, with symptoms resembling the common cold. However we all remember what happened to Jesse Gelsinger. The company claims most patients who have a not too bad prognosis to start with, will show some kind of partial or complete response. Not surprisingly, a lot of foreigners are going to china to get the virus. Are we being unfair to the company only because it originates from China, or is this one of those "stem cell therapy" type shenanigans. This nature news piece weighs in on the issue. In any case China is becoming a major player in the area, and we'll have to get used to the idea of seeing drugs originating there.