p21 RAS and NF

• By CindyLouWho
• Posted October 19, 2009 at 9:29 pm
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Hey you, what are you doing over here! LOL

I'll give your question a try....

These are complicated pathways and mechanisms of which much has been learned and much is still unknown. Basically p-21 RAS has been found to be mutated in a large number of tumor lines (something like a third of all cancers). Now this is what I think happens, or a very watered down version. In order for p-21 to normally be held in check it has to bound to enzymes in the GAP family. The problem is that neurofibromin acts as a RAS-GAP so therefore when neurofibromin is decreased (as in NF) the ability to regulate p-21 ras is lost. The inhibition of GAP results in increased RAS. Which is just a complicated way of saying that when the tumor supressor is damaged, the ability to supress tumors is affected. Except it gets more complicated than just that and RAS may only be a piece of the tumor picture. Research continues to branch out and consider additional aspects of these pathways.

http://herkules.oulu.fi/isbn9514271106/html/x275.html
[quote]The best-known function of the NF1 protein is to act as a Ras-GAP. The Ras-GAP proteins stimulate the intrinsic Ras-GTPase to hydrolyze Ras attached GTP to GDP and inactivate the Ras by doing this (Fig. 2). The Ras-GAP function of the NF1 protein was first suggested after gene cloning and the identification of a region homologous to other Ras-GAP proteins (Ballester et al. 1990, Xu et al. 1990b). p120GAP and GAPIII are the closest relatives, sharing ~30% identity with the GAP region of the NF1 protein. The NF1 protein has been shown to interact with Ras-GTP and to stimulate its GTPase activity (Martin et al. 1990, Xu et al. 1990a, Bollag & McCormick 1991). The affinity of the NF1 protein to Ras-GTP is higher than that of p120GAP, but the stimulation of the intrinsic GTPase activity of Ras is less marked compared to p120GAP (Martin et al. 1990, Bollag & McCormick 1991). The NF1 protein also binds to oncogenic Ras, but is not able to stimulate its intrinsic GTPase activity (Xu et al. 1990a, Bollag & McCormick 1991). Furthermore, certain lipids (e.g., arachidonic acid, phosphatidic acid, stearic acid, oleic acid, phosphatidylinositol-4,5-bisphosphate, some n-6 and n-3 polyunsaturated fatty acids) decrease the GAP activity of the NF1 protein (Bollag & McCormick 1991, Golubic et al. 1991).

Elevated Ras-GTP levels have been demonstrated in some cells and tissues obtained from NF1 patients. Elevated Ras-GTP levels have been demonstrated in Schwann cells, primary leukemias, malignant schwannomas, neurogenic sarcomas and dermal neurofibromas (Basu et al. 1992, Yan et al. 1995, Bollag et al. 1996, Guha et al. 1996, Sherman et al. 2000). However, low levels of NF1 protein have not been shown to lead to increased Ras-GTP levels in various cell types, including melanomas, neuroblastomas, melanocytes and fibroblasts (Boddrich et al. 1995, Griesser et al. 1995, Sherman et al. 2000). Transfection studies have shown that overexpression of NF1 protein may lead to suppression of cell growth, transformed phenotype and decreased tumorigenicity without any change in Ras-GTP levels, suggesting that the NF1 gene can act independently of GAP activity (Johnson et al. 1994, Li & White 1996). Furthermore, in Drosophila, the NF1 protein seems to be a regulator of the cAMP-PKA-dependent signaling pathway instead of the Ras pathway (Guo et al. 1997, The et al. 1997, Tong et al. 2002). Defective calcium signaling has also been demonstrated in keratinocytes cultured from NF1 patients (Korkiamaki et al. 2002).

Taken together, the NF1 protein seems to be involved in the regulation of the Ras-MAPK pathway. However, the GAP region of the NF1 protein is only a fraction of the length of the total protein product. Consequently, it is likely that the NF1 protein has functions other than acting as a Ras-GAP. These other functions could involve regulation of the cAMP/PKA pathway or calcium-related signaling. The complexity of the regulation of the NF1 protein is shown by studies demonstrating various subcellular localizations for it.
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This second article is one that I already posted for you some time ago on your growth thread on the CTF site.

http://mednews.wustl.edu/news/page/normal/12134.html
[quote]Gene's newly explained effect on height may change tumor disorder treatment

By Michael C. Purdy


Aug. 11, 2008 -- A mutation that causes a childhood tumor syndrome also impairs growth hormone secretion, researchers at Washington University School of Medicine in St. Louis have found.

The discovery provides new insights into an old mystery, revealing why patients with neurofibromatosis type 1 are frequently shorter than their peers. The surprising details have led scientists to consider modifying their search for treatments for the inherited disorder, which is caused by a mutation in the neurofibromin 1 (NF1) gene and is characterized by an increased risk of cancer.

"We've learned that the NF1 gene affects stature through a different pathway than the one we've previously focused on to understand cancers in patients with neurofibromatosis type 1," says David H. Gutmann, M.D., Ph.D., a Washington University neurologist who treats individuals with neurofibromatosis at St. Louis Children's Hospital. "Given that this second pathway has been linked to cancer in other disorders, we may need to consider the possibility that it is contributing to these tumors and alter our treatment goals accordingly."

The results appear online in the journal Human Molecular Genetics.

Neurofibromatosis 1 affects more than 100,000 people in the United States and is one of the most common tumor predisposition syndromes. The severity of the condition varies.

The NF1 protein, called neurofibromin, influences a number of different growth control pathways. Until now, much research focused on neurofibromin's effects on RAS protein activity, which is linked to cell growth, proliferation and cancer. Normally, NF1 deactivates RAS proteins. In its absence, scientists believe unchecked RAS can promote cancer development.

To learn more, Gutmann's lab created a line of mice in which stem cells in the brain do not make the NF1 protein. They found that these mice were significantly smaller than normal and failed to grow and gain weight after birth.

Balazs Hegedus, Ph.D., a postdoctoral researcher in Gutmann's laboratory, noticed that the pituitary glands, which produce growth hormone, also were unusually small in these mice. The amount of a second hormone that triggers growth hormone release was also greatly reduced.

"We wanted to know if we could blame this on RAS protein activity, so we generated new mice with normal levels of neurofibromin expression, but increased levels of RAS activation in brain stem cells," says Gutmann, the Donald O. Schnuck Family Professor of Neurology, and director of Washington University Neurofibromatosis Center. "However, those mice were normal."

NF1 also increases brain levels of cyclic AMP (cAMP), an important signaling molecule. Working again with mice that do not make the NF1 protein, researchers fed pregnant mice and their newborns an agent that increased cAMP levels. The baby mice were closer to normal size, even though they still lacked neurofibromin in brain stem cells. Gutmann suspects the mice didn't grow to normal size because dietary supplementation of cAMP levels cannot match the natural ability of neurofibromin to control cAMP levels.

Gutmann is intrigued by the connection to cAMP. Research in other disorders has begun to build a number of associations between cAMP and tumor formation. Gutmann's laboratory and others have treatments in the works for neurofibromatosis 1 that restore the inhibitory effect neurofibromin normally has on RAS, but the new results may mean treatments are also needed to restore neurofibromin's effects on cAMP levels.

"What we've learned also may help us gain insight into other disease processes," Gutmann notes. "There are a number of other rare genetic abnormalities that cause short stature, and this same pathway may be involved."

To follow up, Gutmann plans additional studies to explore the role of the NF1 gene in the pituitary gland and the hypothalamus, a brain region that controls the pituitary gland production of growth hormone.
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Anyway, I have to run but I hope that helps.

Cindy

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• By sweetiecat
• Posted October 20, 2009 at 12:37 am
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That is some heavy reading...

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• By sami_mom
• Posted October 20, 2009 at 9:33 am
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Thanks Cindy,
Yes it helps tons. I knew you would have the answers. It is interesting and I wish I could talk to some of these researchers. I spoke to a doctor who told me p21 ras is attached to cell membranes by a derivative of cholesterol called farnesyl. By reducing cholesterol production you decrease farnesyl formation and ras activity. So what this is saying in terms of stature ras increased activity does not matter as much as the lack of Neurofibromin. But what about on tumor growth? Also what about those that have increase ras because of the farnesyl (if that happens) and they do not have the neurofibromin to modify?

Tracy

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• By CindyLouWho
• Posted October 20, 2009 at 10:41 am
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Tracy, I left you a PM at the other site. Sorry I've been down with the flu so I hope it makes sense. The cholesterol RAS link has been known for some time and goes well beyond NF research. NF research has also been making use of farnesyl transferase inhibitors. In some cases they are even looking at combining that with lovastatin to treat MPNST. So this has been known for some time. I think the NF research is now also looking at additional factors such as cAMP. Neurofibromin controls more than just RAS. This article describes the idea of branching out beyond RAS to address different tumors/complications of NF.

http://www.scientificblogging.com/news_account/nf1_gene_essential_to_brain_ development_also_implicated_in_pediatric_brain_tumors#

I've posted this one before too but it makes some interesting points about NF not being involved in cholesterol metabolism.

http://jfajansenphd.googlepages.com/08_jansen_jama.pdf

Did you learn anything else interesting or new at the meeting?

Cindy

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