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'Kiss of Death' Discoverers Get Nobel Prize
baldinux writes "Science Daily has written an article describing the cellular process of regulated protein degredation, which has landed three people the Nobel Prize in Chemistry. According to the article, this finding could greatly help researchers understand ubiquitin-mediated protein degradation, making it possible to develop drugs to treat cervical cancer, for example."
From the first couple of comments, it seems people don't know what the heck this is talking about. Let me explain:
The human body has a natural mechanism for recycling proteins. What nobody understood, however, was how it knew what proteins to recycle - after all, if proteins were just recycled randomly we'd all be globs of jelly.
So then these guys came along and figured it out: when the body wants to recycle a protein, it attaches another protein as a label, called ubiquitin.
The science isn't exactly new - 1980s - but it was significant, and best of all, pure research. (So you can stop with the whining about drugs)
Congrats to these guys. It really is an honor for a University to have a Nobel Laureate in their staff, and UC Irvine just got one. =]
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I recently learned (through an unpleasant personal, but not-quite-that-personal, experience) that HSV, an STD, is the "major cause of cervical cancer".
Watch out, guys. Especially watch out ladies.
-Peter
The cancer part is interesting - I hadn't thought about that in my previous post. The idea is to engineer ubiquitin to attach itself to cancer cells, therefore causing the body to kill the proteins inside, effectively killing the cells. (Well, cells are proteins.)
It's a very interesting concept, not limited to any type of cancer as far as I know, but again, this is 1980s research, not brand new as the article suggests, but still exciting.
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(Late) Frederick Reines at the School of Physics and Astronomy at UCI:
1995 Nobel Laureate Frederick Reines [1918-1998] Distinguished Professor Emeritus Elementary Particle Physics
Professor Reines earned his M.E. and M.S. degrees from Stevens Institute of Technology in Hoboken, New Jersey and his Ph.D. from New York University in 1944. He was a member and then Group Leader in the theoretical division of the Los Alamos Scientific Laboratory from 1944 to 1959. He was a Professor and Head of the Physics Department at Case Institute of Technology from 1959 to 1966 and Professor and founding Dean of Physical Sciences at UCI.
Professor Reines' work has been recognized by membership in the National Academy of Sciences and many other awards including the National Medal of Science. He was known for his work on the detection and study of the neutrino. We all mourn his passing in 1998.
An Indian-American Hindu committed to non-violent thought/speech/action alarmed by the global explosion of radical Islam
There are many, many different types of cancer. At least one for every tissue in the body. Cancers retain many of the properties of the parent tissue. Many breast cancers for instance, are estrogen dependant. So an estrogen antagonist can help shrink many breast cancers. This wouldn't work at all for skin/lung/colon/whatever cancer. I'm not sure about the specifics of cervical cancer, but it's likely there are proteins specifically expressed in cervical tissue that could be targetd for degradation by an engineered ubiquitin ligase.
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You might find the information over at the Nobel website more interresting: http://nobelprize.org/chemistry/laureates/2004/pub lic.html.
SIG: TAKE OFF EVERY 'CAPTAIN'!!
The FDA approved the first proteasome inhibitor last year (link) It is called velcade or bortezomib.
Not exactly like in programming. As far as I know (I'm not a programmer) the OO languages use object disposal to free up resources. Degradadtion of macromolecules like proteins (through ubiquitine pathway discovered by the Nobel laureates) or RNAs is, however, primarily a way to control different cellular processes. The cell adjusts to different needs by altering the set of proteins that it contains (called the proteome). If proteins were infinitely stable there would be no way of up- or downregulating their levels - once made they would stay there forever. So proteins (and mRNAs that encode them) have a built-in end-of-life mechanism that, together with varying the synthesis rate, makes regulation possible. There is more to it - protein degradation is also used to remove damaged or incorrectly made proteins. So, to sum it up: protein degradation is essential for both regulation and quality control of cell's proteins. Even though there are no direct practical applications so far, the significance of the discovery is great - we do know that if something goes wrong with the cell's regulatory mechanisms we get cancer, understanding ubiqutination brings us closer to understanding how cancer happens.
This is very interesting. Prions, supposedly the cause of CFJDv (The human version of Mad Cow disease) could be targeted. Cancer cells could be neutralized. It's really very broad, the possibilities.
Now they just need more funding!
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The biggest problem to developing any potential theapies from these groundbreaking discoveries is to figure out how to target particular proteins or classes of proteins. There are numerous E3 ubiquitin ligases in cells that target a varety of proteins for degradation. However, the molecular mechanisms by which this recognition takes place is still rather uncertain. The structure of the molecular interaction must be determined at atomic resolution (A difficult process which commonly uses X-ray crystallography and very, very intensive computing).
I see two methods which would lead to useful therapies:
The first is the simplest and will therefore also most likely be the first viable strategy: harnessing natural ubiquitin ligases to target and downregulate harmful proteins. This means that any therapies will be limited to natural ubiquitination processes. Humankind will find ways to make these reactions better, or ways stimulate them in diseased cells.
The second approach is de novo design. Once the structure of the target is determined, enzymes can be desgined to target it for ubiquitination/degradation. However, this requires an understanding of biochemistry far beyond what currently exists. Not only does the therapeutic enzyme have to recognize the target, but it must also catalyze the ubiquitination reaction. At this time, I do not believe that anyone has designed a functional protein-based enzyme from the ground up. This technique has greater potential, as we could target ANY protein we dislike, but we are not quite able to implement it yet.
"Me fail English, that's unpossible." --Ralphie
Targeted protein degradation has applicaitons beyond anti-cancer therapies. Alzheimer's Disease seems to be caused by the build-up of amyoloid beta protein in neurons, which is due to the failure to degrade this protein. One potential therapy is to use other ubiquitin ligases to target amyoloid beta for degradation as a method to break up protein plaques.
Similarly, antiviral potential exists as well. For example, if we could engineer ubiquitin ligases to target HIV proteases (The target of the protease inhibitor component of anti-HIV "cocktails"), we would have another method to hamper viral replication.
As with all new developments, however, there exist numerous problems that must to be overcome before we see practical and clinical results.
"Me fail English, that's unpossible." --Ralphie
Biochemists could, I presume, tailor ubiquitin to grab up undesirable proteins and still have the degradation function work.
Well, you'd want to play with the enzyme that attaches the ubiquitin tag to the target protein, the "ubiquitin ligase." It's hard to say how exactly you'd do that until gene therapy pans out. You could potentially activate or deactivate existing ligases, but you'd have to know which one targets the protein of interest, and hope that it doesn't destroy too much else.
It's also interesting to note that ubiquitin is not only a "kiss of death" Substrates destined for the proteasome are polyubiquitinated(in series). Monoubiquitin can serve as an intracellular trafficking signal, or a molecular switch turning an enzyme on or off in much the same way as phosphorylation does. There's still a lot of work to do to find out the fine details of who gets how many ubiquitins and what exactly it does.
Biochemists could, I presume, tailor ubiquitin to grab up undesirable proteins and still have the degradation function work.
Interestingly there are diseases caused by malfunctioning ubiquitin ligase. The mental retardation disorder Angelmans disease is caused by a knockout of the ubiquitin ligase E6-AP on the maternal chromasome. Due to genetic imprinting, the maternal form is only used in the brain, so this is like a brain specific knockout of this ligase.
It's not known exactly what targets of E6-AP are responsible for the disease, but in a mouse model the protein CaMKII was hyperphosphorylated and deactivated. CaMKII is one of the major proteins in the brain (approx 10% of brain protein by mass), and it is essential for Long Term Potentiation, a major mode of synaptic plasticity. This is exciting because it's the first time that CaMKII and LTP deficiancies have been linked to learning in humans. Protein phosphatase activity was also reduced in these brains, suggesting a phosphatase deactivation as the proximal cause of CaMKII hyperphosphorylation. Elucidating how E6-AP knockout leads to phosphatase dysregulation will be a large part of my thesis research, if I can ever get some phospho-CaMKII antibodies that work...
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Here Ciechanover & Herhsko got the Lasker prize for ubiquitination a few years back. Getting the Lasker prize is a pretty good indicator for receiving the Noble as well.
inhibit proteasome activity. One might argue about how useful it is (it is certainly not a miracle cure) but vecade (bortezomib) is already FDA approved. It is pretty clearly the best treatment available for replased myeloma.
> Is cervical cancer different from other cancer?
One difference is that there is now a vaccine for cervical cancer which is apparantly 100% effective, so it's one of the less important cancers in terms of saving human life in the long run.
http://news.bbc.co.uk/1/hi/health/2495029.stm