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Telomere questions


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#31

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Posted 05 January 2005 - 07:58 AM

Caspase/suicide gene induction is one way. How could we get a T cell worked up?
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#32 John Schloendorn

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Posted 05 January 2005 - 08:38 AM

Strong cell surface antigen? T-cell co-receptor ligand overexpression? FAS ligand overexpression? Designer-ligand to bind engineered T-cells? Secretion of inflammation inducing factors?
Anyways, you owe me an inducer.
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#33 John Schloendorn

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Posted 05 January 2005 - 09:59 AM

How is the following:
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...
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#34 John Schloendorn

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Posted 05 January 2005 - 10:06 AM

Nah, we would get trouble with rapid division during T-cell clonal expansion, and turnover in the gut, this really sucks, I withdraw
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#35

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Posted 05 January 2005 - 07:27 PM

A couple of putative inducers relevant to melanoma are MUC18 and MCAM.

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.
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#36 John Schloendorn

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Posted 06 January 2005 - 03:09 AM

T-Cells: So? Sad thing. Are you suggesting to express foreign MHCs from cancer candidate cells to attract killer cells? The choice of the ligand should depend on typical induction kinetics for and affinities of complementary T-Cell receptors. Any data?

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.
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#37

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Posted 06 January 2005 - 02:29 PM

There is no more fiercer and committed immune response known than that directed towards an allogeneic HLA type.

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.
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#38 John Schloendorn

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Posted 07 January 2005 - 03:26 AM

Sounds good, thanks for the teaching. So we have put together a good bunch of ideas how to get rid of the suspicious cells. But we still do not have much of a clue how to identitfy them as suspicious.
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.

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#39 Flying Hermit

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Posted 17 July 2010 - 03:24 PM

Questions regarding telomerase activation:

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
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#40 Flying Hermit

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Posted 19 July 2010 - 09:23 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

Edited by trefoglio, 19 July 2010 - 09:24 PM.

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#41 Anthony_Loera

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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.

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#42 Anthony_Loera

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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.
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#43 treonsverdery

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Posted 10 February 2012 - 08:40 PM

well, how about this ubiquination tags proteins to be recycled. a biochem textbook (Voet) says proteins with n-terminal amino acids (asp, leu, lys, phe ) last just 2 or 3 minutes prior to being ubiquinated wheras those with (ala, gly, met, ser, val ) last 10 hours. That is 200 times more residence at the cytosol. So changing just one codon of the telomerase gene could make a version that lasts 200 times longer, giving the body a huge amount of functional telomerase. It may be possible to do a gene therapy version, where telomerase with 1 codon changed occurs at every transfected cyte, lengthening telomeres.

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.

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#44 treonsverdery

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Posted 11 February 2012 - 10:39 PM

well I looked up the telomerase genes TERT, TERC, TEP, TEN1 online at genenames.org TERC has N-terminal glycine, which is durable. The others all have N-terminal methionine which is also durable. There are other telomerase genes as well as telomerase regulating genes, listed. I have not looked to see if any of them are nondurable.

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.
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#45 niner

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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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