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Very exciting article showing a likely link of 2 proteins to Cushings

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The following is a very exciting article located at http://media.pituitary.org/newsletter/dec2006/articles.htm

which is PNA's website.


Basically, it shows that all of these people had the same essential proteins missing. What I would be interested to see is something that would confirm that these essential proteins being missing caused the tumors rather than the tumors causing the proteins to be missing. I will see if I can do some research to see the specifics of this mechanism to confirm if that can happen. If it can't, this could definitely be a very exciting tool at diagnosing people, at or least showing who is at risk.


It seems like it needs a lot more work before it can be used as a diagnostic tool, and it seems it only will show half of the people with such an issue.



What I REALLY want to know, is how many are missing these proteins with no symptoms, no tumors, etc. Because, if very few are missing them without being Cushingoid, then it could be another piece of evidence to diagnose us. I need more evidence, myself, so I am very interested in anything I can get as far as clues.


Granted, even if only Cushingoid people do have that happen, it would only help half of us (and it could even be smaller for us since we are that hard to diagnose group), but any new tests would be great.


But, to be helpful, these essential proteins would have to exist in almost all who do not have Cushings. Such as, 10% of all people have tumors so that alone does not help us that much. Far too many with tumors are definitely not cushingoid, most are asymptomatic.


I will tell you anything I find out; would love if anyone else heard anything as well.


Researchers Make Progress Against Cushing?s Disease


Recently the PNA received a very nice letter from a pituitary research team in Montreal. We pass it on here, as it explains the progress being made in the fight against Cushing?s, one of the most insidious forms of pituitary disease.


Dear Mr. Knutzen,


As a pituitary researcher, I have appreciated the great work you and the PNA do to bridge knowledge between patients and science / medicine. This kind of outreach must be very comforting for patients and I can assure you that it puts a very different light on the work we do in the lab to understand pituitary function and diseases.


I have been active in the field for over 30 years since my PhD and my lab contributed by the discovery of Pitx1 (pituitary homeobox transcription factors) and of Tpit (pituitary Tbox factor) that accounts for 2/3rds of inherited congenital isolated ACTH deficiency (IAD). In fact, we predicted this condition, found the genetic cause and finally provided its first exhaustive clinical description last year.



We published this week a paper that provides totally new insight into the mechanism of Cushing disease and that will hopefully lead to understand its origin and pathogenesis. The work should also help in designing novel therapeutic approaches based on the molecular targets that are disrupted in the tumor cells that cause Cushing disease.


Here is a short text, which may be helpful in summarizing the discovery:




Cushing disease is caused by pituitary tumors that produce excessive amounts of the pituitary hormone ACTH, leading to excessive synthesis of glucocorticoids by the adrenal glands. Many symptoms of Cushing disease result from these high levels of glucocorticoids and they include fat accumulation, high blood pressure and predisposition to diabetes and osteoporosis. Normally when blood glucocorticoids are elevated, they exert a negative feedback effect on the production of pituitary ACTH, thus closing a regulatory loop that keeps both ACTH and glucocorticoid levels in balance. The hallmark of the pituitary corticotroph adenomas that cause Cushing disease is that these tumor cells are no longer sensitive to the feedback action of glucocorticoids. This hormone resistance is likely the first event in the formation of the pituitary tumors. A Montr?al research group led by Dr. Jacques Drouin and including collaborators in Canada, France, the Netherlands and United States, has just discovered essential components of the molecular mechanism for glucocorticoid feedback control of pituitary ACTH gene expression. Indeed, the Montr?al group discovered a large complex made of several proteins that are essential for negative feedback by glucocorticoids; this complex includes proteins that are known for their role in the control of gene expression and remodeling of chromosome (chromatin) structure. One of these essential proteins, BRG1, is also known to be a tumor suppressor. Consistent with the essential functions of these proteins in negative feedback by glucocorticoids, the researchers found that either of these proteins is no longer correctly expressed in about half of pituitary tumors from Cushing disease patients (both adult and pediatric) as well as from dogs with Cushing disease (for unknown reasons, this condition is more frequent in dogs than humans), thus providing a molecular explanation for the hormone resistance that characterizes theses tumors.


This work brings the first molecular insight into the mechanisms of Cushing disease. Beyond explaining hormone resistance, it also identified genes that likely initiate the process of tumor formation. This novel insight will lead to the rational design of new therapeutic approaches for the more efficient management of patients with Cushing disease. This work is published in the 15 October issue of Genes and Development (Bilodeau et al, Genes Dev 2006, 20:2871-2886) and it was supported by grants from the National Cancer Institute of Canada and from the Canadian Institutes of Health Research.


Please do not hesitate to contact me if you need some clarifications on the work that should be of primary interest to many PNA Newsletter subscribers.


For the full text of the paper, please go to: http://www.genesdev.org/current.shtml#RESEARCH_PAPERS



Jacques Drouin, FRSC

Laboratoire de G?n?tique mol?culaire

Glaxo Smith Kline Chair in Molecular Genetics

Institut de recherches cliniques de Montr?al

110 Avenue des Pins ouest

Montr?al, Qc

Canada H2W 1R7

Tel.: 514-987-5680 FAX : 514-987-5575

email : jacques.drouin@ircm.qc.ca



(I also apologize if anyone already posted it; ie MaryO in a news letter...I miss quite a few posts/journals these days)

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  • Member of the 1000 Post Club

I also appreciated the article.


When you think about all of the disease or syndromes that are known to be linked to Cushings it makes sense that there may be a common underlying biochemical process that is common to all or several of them.



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