Telomere questions
#31
Posted 05 January 2005 - 07:58 AM
#32
Posted 05 January 2005 - 08:38 AM
Anyways, you owe me an inducer.
#33
Posted 05 January 2005 - 09:59 AM
Most cancers divide more rapidly than stem cells, say typically within 18 hours. Most stem cells do not divide that rapidly, or at least, we could perhaps tolerate the loss of the few that try to. So we need an inducible System that is sensitive to the time since the last division.
Let's start with E2F, which is a key S-phase transcription factor with a variety of target promoters. Furthermore we introduce a number of delay-transcription factors D(N), which can be really any transcription factors that do not recognize anything wild-type in the given cell type. And we introduce X-Y, which is a dimeric transcription factor, that again recognizes nothing wild-type.
Now we tweak everything so that we get the following transcription cascades:
E2F -> Y
E2F -> D(1) -> D(2) -> D(3) -> X (takes 18 hours until X is expressed)
X-Y -> Suicide
So Y is expressed during every S-phase, and X is expressed 18 hours after S-phase. Thus, if S-phase was only 18 hours ago, and the cell attempts to initiate another S-phase, X and Y get together and it suicides.
Hmm, I reckon if we're lucky, all we do is select for cancers to divide less rapidly, which may be of some therapeutic benefit. However, rapid division may be something that is acquired only at a late stage in cancer evolution, and thus plenty of potential exists to select against the system at any point. So forget about it...
#34
Posted 05 January 2005 - 10:06 AM
#35
Posted 05 January 2005 - 07:27 PM
Unfortunately, epithelial cells, particularly in the GI tract also have very high division rates as you mentioned.
Back to T cells. They really hate certain grafts.
#36
Posted 06 January 2005 - 03:09 AM
Inducer: So, we have a cell surface receptor overexpressed. Where are you going from here? The receptor will help us only if we find a promoter that activates selectively when the receptor is overexpressed.
What is more, I hate to discourage your inducer, but I take it that MUC18/MCAM overexpression starts late stage, just prior to metastasis. Thus, the cancer may have enough cells and genomic instability to evolve against any MUC18/MCAM based expression system, no matter how smart it is.
#37
Posted 06 January 2005 - 02:29 PM
The inducing protein is intracellular, as it needs to be to activate the promoter. Consequently it never needs to be associated with the plasma membrane, let alone being anchored on the external side, which is what present approaches of immunotherapy rely on.
You are quite right, MUC18/MCAM does start late and prior to metastasis. Be aware, however, that metastasis cannot be effected without MUC18/MCAM. Consequently, irrespective of what mutation/evolutionary path a tumor cell may take it will not help it achieve metastatic potentiation without the unregulated expression of MUC18/MCAM.
But one does need to wait until such a late stage in the process of tumorigenesis to alert the immune system since earlier overexpressed (intracellular) proteins can be chosen as inducers.
#38
Posted 07 January 2005 - 03:26 AM
As for MUC18/MCAM: As with any late-stage receptor, microevolution will select for our suicide gene to escape the signalling cascade, no matter how required the receptor is. All it takes is one chromosome breakage, or insertion event between our suicide gene and its promoter. With the number of cells in a tumor (billions) approaching the number of base pairs in a cell (billions), this becomes too likely to make the system reliable.
Countermeasures would be the use of earlier stage expression changes as a trigger, multiple suicide systems, or multiple copies of the same system. This increases genetic payload, but should not be a problem with mammalian artificial chromosomes (MACs). I think all it takes to large-scale test such a system in mice is already there. One could try a complete hematopoietic ablation, rescue with stem cells modified as discussed and measure leukemia incidence. I bet we could reduce it by some orders of magnitude.
Alternatively, do transgenesis and try to hit all cancers, with a MAC brimming with different suicide systems.
We still need to detail a few inducible systems, but that should be possible to work out.
Edited by John Schloendorn, 07 January 2005 - 05:24 AM.
#39
Posted 17 July 2010 - 03:24 PM
Biotivia has BioSpan+ product, that contain 150 mg astragaloside IV ( telomerase acivator ) and also
telomerase inhibitors like tumeric, silymarin and resveratrol.
1. do you think this product is safe to use and how long periods?
2. Do you think it will activate telomerase or not ( because of telomerase inhibitors) ?
thanks for answers,
Tristan
trefoglio@gmail.com
#40
Posted 19 July 2010 - 09:23 PM
telomerase inhibitor for healthy cells? If not then
it may be great idea to use cycloastragenol and resveratrol
at same time...
To the Dream,
Tristan
Edited by trefoglio, 19 July 2010 - 09:24 PM.
#41
Posted 20 July 2010 - 12:49 PM
Can anyone show me study about resveratrol acting as
telomerase inhibitor for healthy cells? If not then
it may be great idea to use cycloastragenol and resveratrol
at same time...
To the Dream,
Tristan
There is non-published data, however your comment of 'hope', doesn't make practical sense here regarding combining inhibitors and activators.
Please continue to post here were you originally asked your question:
http://www.imminst.o...ndpost&p=419814
The conversation on this thread between John, ddhewitt and prometheus does not revolve on supplements.
Edited by Anthony_Loera, 20 July 2010 - 12:50 PM.
#42
Posted 20 July 2010 - 12:51 PM
Can anyone show me study about resveratrol acting as
telomerase inhibitor for healthy cells? If not then
it may be great idea to use cycloastragenol and resveratrol
at same time...
To the Dream,
Tristan
There is non-published data, however your comment of 'hope', doesn't make practical sense here regarding combining inhibitors and activators.
Please continue to post here were you originally asked your question:
http://www.imminst.o...ndpost&p=419814
The conversation on this thread between John, Marcus, LifeMirage and prometheus does not revolve on supplements.
#43
Posted 10 February 2012 - 08:40 PM
pubmed doesn't have anything on does telomerase get ubiquinated, what do changes to the rate of telomerase ubiquination do?
I suppose the thing to do is to find the n-terminal amino acid of telomerase at a database I do not know which one though.
Does anyone out there know the location of the telomerase codon sequence online
Edited by treonsverdery, 10 February 2012 - 08:59 PM.
#44
Posted 11 February 2012 - 10:39 PM
It is possible that a normal codon other than methionine (melting point 281) is more durable giving benefit. Valine has a higher melting point (298), is also published as durable. There is a possibility that either Valine or Se-methionine may be more durable as well telomerase wise.
#45
Posted 12 February 2012 - 01:15 AM
It is possible that a normal codon other than methionine (melting point 281) is more durable giving benefit. Valine has a higher melting point (298), is also published as durable. There is a possibility that either Valine or Se-methionine may be more durable as well telomerase wise.
The melting point of the isolated amino acid has no impact on the stability of a protein that it's a part of.
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