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 L'enzyme SIRT1

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Denis
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Nombre de messages : 15767
Date d'inscription : 23/02/2005

MessageSujet: Re: L'enzyme SIRT1   Sam 24 Nov 2012 - 14:25

29 juin 2012

Abstract

Because we found in a recent study that pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, induces a rapid proliferation of pancreatic cells by up-regulation of β-catenin, we postulated that β-catenin might be a target molecule for pancreatic cancer treatment. We thus speculated whether SIRT1, known to target β-catenin in a colon cancer model, suppresses β-catenin in those pancreatic cancer cells that express PAUF (Panc-PAUF).

Parce que nous avons découvert dans une étude récente que le facteur de régulation à la hausse du cancer du pancréas ou PAUF induisait une rapide prolifération des cellules pancréatique en augmentant ß-catenin, nous avons postulé que la molécule ß-catenin pourrait être une cible pour le traitement du cancer du Nous nous alors demandé si SIRT1, connu pour cibler ß-catenin dans une forme de cancer du colon, supprimerait ß-catenin dans la forme de cancer du pancréas qui exprime PAUF.


We further evaluated whether such suppression would lead to inhibition of the proliferation of these cells. The ectopic expression of either SIRT1 or resveratrol (an activator of SIRT1) suppressed levels of β-catenin protein and its transcriptional activity in Panc-PAUF cells. Conversely, suppression of SIRT1 expression by siRNA enhanced β-catenin expression and transcriptional activity. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for reduction of β-catenin.

Nous avons évalué plus avant qu'une telle expression conduirait à l'inhibition de la prolifération des cellules. L'expression ectopique de SIRT1 ou de resveratrol (un activateur de SIRT1) a supprimé les niveaux de la protéine ß-catenin et son activité trancriptionnelle. À l'opposé, la suppression de SIRT1 par un petit ARN interférent augmente l'expression de ß-catenin et son activité de transcription. Une analyse de SIRT1 montrre que sa localisation dans la cellule n'importe pas pour sa réduction.

Treatment with MG132, a proteasomal inhibitor, restored β-catenin protein levels, suggesting that SIRT1-mediated degradation of β-catenin requires proteasomal activity. It was reported that inhibition of GSK-3β or Siah-1 stabilizes β-catenin in colon cancer cells, but suppression of GSK-3β or Siah-1 using siRNA in the presence of resveratrol instead diminished β-catenin protein levels in Panc-PAUF cells. This suggests that GSK-3β and Siah-1 are not involved in SIRT1-mediated degradation of β-catenin in the cells. Finally, activation of SIRT1 inhibited the proliferation of Panc-PAUF cells by down-regulation of cyclin-D1, a target molecule of β-catenin. These results suggest that SIRT1 activation may be a therapeutic strategy for treatment of pancreatic cancer cells that express PAUF via the down-regulation of β-catenin.

Le traitement avec MG132, un inhibiteur de protéasome, restaure les niveaux de ß-catenin, ce qui suggère que la dégradation amenée par SIRT1 de ß-catenin requiert une activité des protéasomes. (...) Finalement, l'activation de SIRT1 a inhibé la prolifération des cellules PANC-PAUF en régulant à la baisse la cycline D1, une molécule cible de ß-catenin. Ces résultats suggèrent que l'activation de SIRT1 pourrait être un moyen stratégique pour traiter les cellules cancéreuses du pancréas qui expriment PAUF à travers la régulation à la baisse de ß-catenin.

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MessageSujet: Re: L'enzyme SIRT1   Jeu 13 Jan 2011 - 16:35

(Jan. 13, 2011) — Researchers from the Kimmel Cancer Center at Jefferson and two other institutions have discovered new evidence that suggests the "longevity" protein SIRT1, known for its life-spanning effects in different species, can inhibit the development of a known precursor to prostate cancer, prostatic intraepithelial neoplasia (PIN).


Les chercheurs de plusieurs institutions ont découverte que la protéine de la longévité, SIRT1, peut inhiber peut inhiber le développement d'un précurseur connu du cancer de la PIN.


Results from the study could lead to new cancer prevention drugs that could not only block prostate cancer but promote longevity.

Les résultats pourraient conduire à de nouveaux médicaments pour prévenir le cancer de la qui pourraient arrêter ce cancer et promouvoir la longévité.

The study, published in the February 1 issue of Cancer Research, found that deletion of the Sirt1 gene in mice resulted in PIN lesion formation associated with reduced autophagy, which is the necessary degradation of a cell's own components and most likely essential for tumor suppression.

"Prostate cancer is one of the malignancies that has a very direct relationship to aging," says Richard G. Pestell, M.D., Ph.D., Director, Kimmel Cancer Center and Chairman of Cancer Biology at Thomas Jefferson University. "And these results provide a direct link for the first time between the onset of prostate cancer and the Sirt1 gene that regulate aging."

The results suggest that the Sirt1 gene promotes autophagy and further highlight the role of the protein SIRT1 (the human homologue of the yeast Silent Information Regulator 2 (Sir2) gene) as a tumor suppressor in the prostate. According to Dr. Pestell, "if you inactivate this gene, then you get the prostate cancer precursor, known as PIN. So it tells you that this 'longevity' gene is normally blocking prostate cancer."

Previous studies have found that SIRT1 -- which was discovered about 15 years ago and found to have various life-spanning effects in yeasts, worms, mice and possibly humans -- can both inhibit tumor growth in certain cancers as well as promote it by inactivating the tumor suppressor p53, but its role in regulating prostate gland development and androgen signaling in vivo was unknown.

To better understand SIRT1's role in the development of androgen-responsive tissues, such as the prostate, researchers from Thomas Jefferson University in Philadelphia, worked with the Herbert Irving Comprehensive Cancer Center at Columbia University in New York and the Ottawa Health Research Institute at the University of Ottawa. Dr. Pestell's laboratory carried out a genome-wide microarray, pathway analysis and histology on Sirt1 positive and negative transgenic mice and littermate controls.

The team found that deletion of the Sirt1 gene in mice resulted in PIN formation; features included cellular hyperplasia, increased Ki67 staining, hyperchromatic nuclei and prominent nucleoli, as well as a reduced size in prostate. Gene expression analysis further demonstrated that loss of endogenous Sirt1 inhibited autophagy, which regulates normal gland development.

Des analyses plus approfondies ont démontré que l'expression du gène endogène SIRT1 inhibe l'autophagie qui régule normalement le développement de la glande.

Dr. Pestell's laboratory was the first to show that the androgen receptor is regulated by the deacetylase enzyme (SIRT1) in cell lines in a tissue culture. "So then we asked the question, 'if you take prostate cancer cell lines, and if the androgen receptor promotes growth, and acetylation promotes growth, does the deacetylase inhibit growth?'" After establishing that it in fact did, researchers applied their mouse model to establish the same relationship on the animal level.

Le docteur Pestell a été le premier à montrer que le récepteur androgène est régulé par l'enzyme SIRT1. si nous posons la question : si les récepteurs androgènes promeuvent la croissance du cancer et que l'acetylisation promeut aussi le cancer, est-ce que la désacétylase inhibe cette croissance ? Et nous avon sétabli que oui et les chercheurs ont trouvé cette mêm erelation en faisant des expériences sur des souris.

Since the results of the study suggest that drugs that activate Sirt1 could block prostate cancer, Dr. Pestell explains, his team is now working to test various prevention drugs they've screened for testing in human prostate cancer cells.


Depuis les résultats de l'étude suggèrent que les médicaments qui activent Sirt1 pourraient bloquer le cancer de la , le Dr Pestell explique que son équipe travaille actuellement à tester divers médicaments de prévention qu'ils ont sélectionnés sur les tests de cellules humaines de cancer de la prostate.
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MessageSujet: Re: L'enzyme SIRT1   Lun 5 Nov 2007 - 19:27

They found that stress-inducing agents, such as oxidative stress, recruit a protein called SENP1 that cuts a regulator called SUMO1 away from the enzyme SIRT1 so its activity level drops, says Dr. Yonghua Yang, postdoctoral fellow in the laboratory of Dr. Kapil Bhalla, director of the MCG Cancer Center.

Les chercheurs ont trouvé que des agents qui induisent le stress, comme le stress oxydatif, recrutent une protéine appelé SENP1 qui éloigne un régulateur appelé SUMO1 de l'enzyme SIRT1 ce qui a pour conséquence que le niveau d'actvités de Sirt1 baisse.

This fundamental finding about the relationship between stress and cancer opens the door for treatments that increase SENP1 activity, making it easier for cells that are becoming cancerous to die, says Dr. Yang, first author on a paper published in the November issue of Nature Cell Biology.

Cette découverte fondamental à propos de la relation entre le stress et le cancer ouvre la porte pour des traitements qui augmentent l'activité de SENP1, rendant plus facile pour les cellules de mourir.

"This is one of the things that makes cancer cells so durable, one way they survive so well," says Dr. Yang. "We want to see if we can block that process and make cells die." Increased SIRT1 activity -- which is routinely present in cancer -- even makes cancer cells more resistant to anticancer drugs such as chemotherapy.

"C'est une des choses qui rend le cancer si durable" dit le docteur Yang " Nous voulons voir si nous pouvons bloquer ce processus et faire que les cellules cancéreuses meurent." Cependant L'activité augmentée de SIRT1 --ce qui est routinier dans le cancer --rend le cancer plus résistant aux thérapies anti-cancer.

The complication is that decreasing programmed cell death, or apoptosis, increases longevity, says Dr. Yang. However he now has evidence that SIRT1 -- also under study for its longevity role -- has different targets when it comes to cancer promotion and longevity that will provide distinct targets for manipulating each.

La complication est que ça fait décroitre la mort programmée des cellules, ou apoptose, et ça accroit leur l ongivité, dit le docteur Yang, Toutefois il a maintenant la preuve que SIRT1 --aussi sous étude pour son rôle dans la longivité des cellules -- a différentes cibles pour ce qui est de faire la promotion du cancer et de sa longivité ce qui forunira des cibles distinctes.

"Whether apoptosis is good or bad depends on the circumstances," says Dr. Yang. "But it's good for cancer therapy."

"Savoir si l'apoptose est bonne ou mauvaise dépends des circonstances"

"This paper describes how stress causes desumoylation and sumoylation of SIRT1 and ultimately cancer," says Dr. Bhalla, Cecil F. Whitaker Jr., M.D./Georgia Research Alliance Eminent Scholar in Cancer and a study co-author.

"Stress-inducing agents produce the association of this enzyme,SIRT-1, with the desumoylating enzyme, SENP1, so cells become more resistant to stress-induced apoptosis," says Dr. Bhalla. "Once SIRT1 is desumoylated, it's less active and you want its activity." When SIRT1 is less active, p53, a tumor suppressor gene that also causes apoptosis, becomes more active.

SIRT1, found throughout the body, is a regulator of protein function through a process called acetylation. MCG researchers also found that sumoylation of SIRT1 (combining it with SUMO1) made it more active and sumoylation motif, which enables SUMO1 to combine with SIRT1, is needed to make that happen.

They have added SUMO1 to human cancer cells and increased SIRT1 activity then used SENP1 to cleave it and reduce activity.

Researchers studying the longevity benefits of SIRT1 have found conflicting information in yeast and mice about whether or not SIRT1 is of benefit. Dr. Yang may have found one reason: mice SIRT1 doesn't contain sumoylation motif. When he created sumoylation motif in mice, SIRT1 activity went up. Dr. Yang will do follow up studies to see if these mice live longer but says SIRT1 may simply have a different function in mice than in humans or yeast, also a common research model.

Future studies also include finding a reagent to increase SENP1 activity, Collaborators include researchers at the University of South Florida College of Medicine and the H. Lee Moffitt Cancer Center in Tampa.
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MessageSujet: L'enzyme SIRT1   Lun 5 Nov 2007 - 11:17

Researchers at the University of Texas M. D. Anderson Cancer Center have found a protein that enables cellular survival during periods of low oxygen, or hypoxia, which also is key for development of many kinds of cancer.

Les chercheurs de l'université du Texas ont trouvé une protéine qui permet la survie des cellules durant les périodes d'hypoxie ou de manque d'oxygène qui est la clé du développement de nombreux cancers.

In the Nov. 2 issue of Cell, they report that this protein, known as SENP1 (Sentrin/SUMO-specific protease 1), might provide a basis for future targeted therapies. They have already started to develop an agent to stop SENP1 from working in cells, which could push a tumor to stop growing and to wither away.

Dans le numérode Cell du 2 novembre, ils rapportent que la protéine connue sous le nom de SENP1 (sentrin/SUMO-specific protease 1) pourrait fournir une nouvelle cible pour une thérapie. Ils ont déja commencé à développer un agent pour arrêter SENP1 de faire son opeuvre dans les cellules.

"We believe this emerging pathway of biological regulation plays an important role in cancer development," says the study's lead author, Edward T. H. Yeh, M.D., professor and chair of the Department of Cardiology at M. D. Anderson Cancer Center.

"Nous croyons que ce chemin cellulaire joue un rôle important dans le dévelopement du cancer."

"We had found earlier that high levels of SENP1 can be found in prostate cancer, but we didn't understand why," Yeh says. "Now, knowing that it regulates the entire hypoxic response, we believe it must play a role in other kinds of cancers."

"Nous avons déja trouvé que de hauts niveaux de SENP1 peuvent être trouvé dans le cancer de la prostate, mais nous ne comprenions pas pourquoi" a dit Yeh " Maintenant nous savons que ça réégule l'entière réponse hypoxique et nous croyons que ça peut jouer un rôle dans d'autres cancers aussi.

Researchers believe tumors adapt to low oxygen levels caused by their own rapid growth by turning on molecules that help tumors build a new blood supply. Yeh and colleagues found that SENP1 is needed for that process and that inhibiting it might be one way to turn off tumor growth.

Les chercheurs croient que les tumeurs adaptent leur bas niveaux d'oxygène causé par leur croissance rapide en activant des molécules qui construisent un nouveau réseau de vaisseaux sasnguins. Yeh et ses collèguues ont trouvé que SENP1 est nécessaire pour ce processus et que de l'inhiber pourrait être un moyen d'arrêtre la croissance de la tumeur.

The work described in Cell is a continuation of a series of discoveries in the Yeh lab. The scientists discovered what they dubbed Sentrin and later named SUMO (Small Ubiquitin-related Modifier) proteins. Like their name suggests, these are mighty biological regulators that attach to other proteins in cells to modify their function or to move their location within a cell. Because they attach to many proteins and alter them, they resemble the well-known ubiquitin proteins which, by linking to proteins, target them for eventual break-down.

So far SUMO has been found to alter the function of more than 1,000 proteins, many of which are transcription factors - proteins in the cell nucleus that bind to DNA to help transcribe genetic information.

Yeh discovered SENP1, which snips SUMO off proteins. This dynamic process is called SUMOylation and deSUMOylation, and so far six different SENP family proteins have been found.

Although SENPs can reverse SUMOylation in many cases, their physiological role has not been well defined. In this paper, Yeh, and three colleagues sought to understand the role that SENP1 plays in normal development.

They bred mice to have a single copy of the SENP1 gene, instead of the normal two, and then they bred these mice again. Some of the offspring did not inherit any SENP1, and they all died between day 13 to 15 of the 21 day gestational period. "We found that they had a problem making red blood cells," Yeh says. "They could only make about one-fourth of the blood cells they needed, and that wasn't enough to sustain life."

They looked at why the blood cells were deficient, and found that at that critical stage, blood cells required erythropoietin (EPO), a hormone that regulates blood cell maturation. "If you don't have EPO, red blood cells will die because they cannot mature," he says. That led to their first discovery - that SENP1 regulates EPO.

Regulation of EPO depends on the blood's oxygen level, and in hypoxic conditions, which occurs at that stage of development, transcription factors known as hypoxia inducible factor1" (HIF1") become active.

"These proteins enter the cell nucleus to turn on transcription of the EPO gene," Yeh says. They found that SENP1 controls EPO production by regulating one particular HIF protein, HIF1a. "When there isn't any SENP1, HIF1a is very unstable," he says. "It is not detectable in the embryo, compared to an embryo that has the SNEP1 gene."

It was already known that SUMO plays a role in the hypoxia process, Yeh adds. "We know that when you lower oxygen, HIF1a enters the cell's nucleus, and is quickly modified by SUMO."

But they discovered that there was one more step before HIF1a becomes active, producing EPO proteins to make more blood cells, and other proteins like VEGF that build more blood vessels to seek new sources of oxygen. They found that SENP1 needs to snip SUMO from SUMO-modified HIF1a before HIF1a can be active in transcription.

But that still didn't explain why HIF1a was missing in the nucleus of cells without SENP1. That led them to another, surprising finding - that if SENP1 does not clip off SUMO from SUMO-modified HIF1a when it is inside the nucleus, that SUMO then acts like ubiquitin, targeting destruction of HIF1a.

"This is the first example that SUMOylation of a protein can lead to its destruction," Yeh says. "That goes against the dogma we all believed in: that SUMO can change the location of a cell, but not degrade it. SUMO can do everything under the sun, including what ubiquitin can do. This vastly increases the functions of SUMOylation."

All this makes sense as far as cancer is concerned, Yeh says. HIF1a expression plays a role in many cancers and to date SENP1 has also found to be over-produced in prostate cancer. "This tells us that SENP1 is potentially involved in the overall regulation of tumorigenesis."

If true, Yeh says, that suggests it could become an Achilles heel for cancer. "These findings imply that you could inhibit SENP1 in tumors and let SUMO target HIF1a for destruction," Yeh says. "If tumors can't grow, these cancers could not continue to build a blood supply and grow and thrive."


Dernière édition par Denis le Sam 4 Juin 2016 - 8:39, édité 5 fois
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MessageSujet: Re: L'enzyme SIRT1   Aujourd'hui à 6:32

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