The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1-/- mice

Ismat, Fraz A.; Xu, Jie; Lü, Min; Epstein, Jonathan A.

doi:10.1172/jci28341

Cited by 37 publications

(56 citation statements)

References 54 publications

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“…However, the malignant phenotypes of neurofibromin-deficient MPNST cells cannot be totally rescued by the GAP domain reconstitution alone (38,39). Furthermore, RAStargeted therapeutic approaches, such as S-trans, trans-farnesylthiosalicylic acid, have provided limited efficacy in clinical studies of NF1 (8,40).…”

Section: Discussionmentioning

confidence: 99%

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

Sun

Haddad

Kraniak

et al. 2013

Molecular Cancer Research

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Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcoma that occurs in carriers of germline mutations in Nf1 gene as well as sporadically. Neurofibromin, encoded by the Nf1 gene, functions as a GTPase-activating protein (GAP) whose mutation leads to activation of wt-RAS and mitogen-activated protein kinase (MAPK) signaling in neurofibromatosis type I (NF1) patients' tumors. However, therapeutic targeting of RAS and MAPK have had limited success in this disease. In this study, we modulated NRAS, mitogen-activated protein/extracellular signal-regulated kinase (MEK)1/2, and neurofibromin levels in MPNST cells and determined gene expression changes to evaluate the regulation of signaling pathways in MPNST cells. Gene expression changes due to neurofibromin modulation but independent of NRAS and MEK1/2 regulation in MPNST cells indicated bone morphogenetic protein 2 (Bmp2) signaling as a key pathway. The BMP2-SMAD1/5/8 pathway was activated in NF1-associated MPNST cells and inhibition of BMP2 signaling by LDN-193189 or short hairpin RNA (shRNA) to BMP2 decreased the motility and invasion of NF1-associated MPNST cells. The pathway-specific gene changes provide a greater understanding of the complex role of neurofibromin in MPNST pathology and novel targets for drug discovery. Mol Cancer Res; 11(6); 616-27. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

Sun

Haddad

Kraniak

et al. 2013

Molecular Cancer Research

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“…Although NF1 À/À mice are lethal at E13.5 because of cardiac defect, the CMVCre; HA-GRD; NF1 À/À mice survive to birth with normal cardiac anatomy. However, these mice succumb to death at perinatal period because of overgrowth of neural crest-derived tissues (Ismat et al, 2006). These findings could be interpreted to indicate that not all of the phenotypes seen in NF1 mutations are solely secondary to Ras dysregulation.…”

Section: Biology Of Neurofibrominmentioning

confidence: 94%

“…In addition, Ismat et al (2006) showed that mice expressing the NF1 GRD only partially rescue the phenotypes seen in NF1…”

Section: Biology Of Neurofibrominmentioning

confidence: 99%

Tumor microenvironment and neurofibromatosis type I: connecting the GAPs

2007

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“…Slides were deparaffinized, washed once in PBS, incubated in 0.1 mg/ml Lectin (SIGMA, L-4895) in PBS at room temperature in darkness for 2 h. Then the slides were washed 3 times with PBS, mounted with fluorescent mounting media (Vector Laboratories), and covered with a coverslip. The cell size was measured with image J software as indicated previously (60).…”

Section: Analysis Of Fibrosismentioning

confidence: 99%

Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function

Wang

Patel

Ricciotti

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

110

105

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Nonsteroidal anti-inflammatory drugs selective for inhibition of COX-2 increase heart failure and elevate blood pressure. The COX-2 gene was floxed and crossed into merCremer mice under the ␣-myosin heavy-chain promoter. Tamoxifen induced selective deletion of COX-2 in cardiomyocytes depressed cardiac output, and resulted in weight loss, diminished exercise tolerance, and enhanced susceptibility to induced arrhythmogenesis. The cardiac dysfunction subsequent to pressure overload recovered progressively in the knockouts coincident with increasing cardiomyocyte hypertrophy and interstitial and perivascular fibrosis. Inhibition of COX-2 in cardiomyocytes may contribute to heart failure in patients receiving nonsteroidal anti-inflammatory drugs specific for inhibition of COX-2.arrhythmia ͉ heart failure ͉ knockout ͉ NSAIDs ͉ fibrosis R andomized, placebo-controlled trials indicate that nonsteroidal antinflammatory drugs (NSAIDs) specific for inhibition of cyclooxygense (COX)-2 confer an increased risk of myocardial infarction and stroke (1-5), effects explicable by suppression of COX-2-derived products, such as prostacyclin (PGI 2 ) and prostaglandia E 2 (PGE 2 ) (6). While, the clinical spectrum of hazard is dominated by a predisposition to thrombosis, an additional feature has been congestive heart failure (1-4). NSAIDs may variably increase blood pressure (7): studies in rodents (8, 9) and a meta-analysis of clinical studies (10) suggest that this reflects inhibition of COX-2 and the specificity with which this is attained (11). Elevation of blood pressure by manipulation of the prostaglandin pathway is conditioned by genetic background in rodents (12). However, given this caveat, deletion or inhibition of COX-2 (8, 13) and deletion of the E prostanoid (EP)-2 receptor (14, 15) or the I-prostanoid receptor (IP) (16) for the COX-2 products, PGE 2 and PGI 2 respectively, may each result in hypertension. Indeed, deletion of the IP in these mice also results in cardiac hypertrophy and fibrosis, effects ameliorated by coincident deletion of the receptor for thromboxane A 2 , the TP, a maneuver that does not, alone, affect blood pressure (16). By contrast, inhibition or deletion of COX-1 attenuates the hypertensive response to infusion of angiotensin II (8) or treatment with a COX-2 inhibitor (13). Although placebo-controlled trials provide unequivocal evidence that COX-2-specific NSAIDs confer a cardiovascular hazard, the number of events within each trial are insufficient to permit analysis of covariates. Thus, it is unknown whether congestive heart failure on NSAIDs results solely from or is exacerbated by hypertension.Although suppression of COX-2-derived prostanoids is sufficient to explain the cardiovascular hazard conferred by purposedesigned and older NSAIDs specific for inhibition of COX-2 (17), there has been interest in the possibility that some or all of these effects might reflect ''off target'' effects. One such example was an overview-trial analysis interpreted to suggest that arrhythmia, cardiac arrest, ...

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The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1-/- mice

Cited by 37 publications

References 54 publications

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

Tumor microenvironment and neurofibromatosis type I: connecting the GAPs

Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function

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