Cancer Research Audrey Hepburn Protein Translation and Cancer
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dasgupta, B.
Right arrow Articles by Gutmann, D. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dasgupta, B.
Right arrow Articles by Gutmann, D. H.
[Cancer Research 65, 236-245, January 1, 2005]
© 2005 American Association for Cancer Research

Cell and Tumor Biology

Glioma Formation in Neurofibromatosis 1 Reflects Preferential Activation of K-RAS in Astrocytes

Biplab Dasgupta1, Wen Li1, Arie Perry2 and David H. Gutmann1

Departments of 1 Neurology and 2 Pathology (Neuropathology), Washington University School of Medicine, St. Louis, Missouri

Request for reprint: David H. Gutmann, Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: 314-362-7379; Fax: 314-362-2388. E-mail: gutmannd{at}neuro.wustl.edu.

Children with the tumor predisposition syndrome, neurofibromatosis 1 (NF1), develop optic pathway gliomas. The NF1 gene product, neurofibromin, functions as a negative regulator of RAS, such that NF1 inactivation results in RAS hyperactivation. Recent studies have highlighted the divergent biological and biochemical properties of the various RAS isoforms, which prompted us to examine the consequence of Nf1 inactivation in astrocytes on RAS isoform activation in vitro and in vivo. In this report, we show that only K-RAS is activated in Nf1–/– astrocytes and that activation of K-RAS, but not H-RAS, accounts for the proliferative advantage and abnormal actin cytoskeleton–mediated processes observed in Nf1–/– astrocytes in vitro. Moreover, dominant inhibitory K-RAS corrects these abnormalities in Nf1–/– astrocytes invitro. Lastly, we show that Nf1+/– mice with astrocyte-specific activated K-RAS expression in vivo develop optic pathway gliomas, similar to our previously reported Nf1+/– mice with astrocyte Nf1 inactivation. Collectively, our results show that K-RAS is the primary target for neurofibromin GTPase-activating protein activity in vitro and in vivo and that K-RAS activation in astrocytes recapitulates the biochemical, biological, and tumorigenic properties of neurofibromin loss.

Key Words: Optic pathway gliomas • NF1, neurofibromatosis • GTPase-activating protein • farnesyltransferase inhibitor; geranylgeranyltransferase inhibitor • K-RAS • 00-00-02 Brain/central nervous system cancers • 02-05-01 Mechanisms and signaling events




This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
C. Gregorian, J. Nakashima, S. M. Dry, P. L. Nghiemphu, K. B. Smith, Y. Ao, J. Dang, G. Lawson, I. K. Mellinghoff, P. S. Mischel, et al.
PTEN dosage is essential for neurofibroma development and malignant transformation
PNAS, November 17, 2009; 106(46): 19479 - 19484.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
T. W. Abel, C. Clark, B. Bierie, A. Chytil, M. Aakre, A. Gorska, and H. L. Moses
GFAP-Cre-Mediated Activation of Oncogenic K-ras Results in Expansion of the Subventricular Zone and Infiltrating Glioma
Mol. Cancer Res., May 1, 2009; 7(5): 645 - 653.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
S. S. Houshmandi, R. J. Emnett, M. Giovannini, and D. H. Gutmann
The Neurofibromatosis 2 Protein, Merlin, Regulates Glial Cell Growth in an ErbB2- and Src-Dependent Manner
Mol. Cell. Biol., March 15, 2009; 29(6): 1472 - 1486.
[Abstract] [Full Text] [PDF]

Home page
 J Child NeurolHome page
D. H. Gutmann
Using Neurofibromatosis-1 to Better Understand and Treat Pediatric Low-Grade Glioma
J Child Neurol, October 1, 2008; 23(10): 1186 - 1194.
[Abstract] [PDF]

Home page
 Hum Mol GenetHome page
B. Hegedus, T.-H. Yeh, D. Y. Lee, R. J. Emnett, J. Li, and D. H. Gutmann
Neurofibromin regulates somatic growth through the hypothalamic-pituitary axis
Hum. Mol. Genet., October 1, 2008; 17(19): 2956 - 2966.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
G. Ambrosini, H. S. Cheema, S. Seelman, A. Teed, E. B. Sambol, S. Singer, and G. K. Schwartz
Sorafenib inhibits growth and mitogen-activated protein kinase signaling in malignant peripheral nerve sheath cells
Mol. Cancer Ther., April 1, 2008; 7(4): 890 - 896.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
B. Hegedus, D. Banerjee, T.-H. Yeh, S. Rothermich, A. Perry, J. B. Rubin, J. R. Garbow, and D. H. Gutmann
Preclinical Cancer Therapy in a Mouse Model of Neurofibromatosis-1 Optic Glioma
Cancer Res., March 1, 2008; 68(5): 1520 - 1528.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Neuroradiol.Home page
F.J. Wippold II, M. Lubner, R.J. Perrin, M. Lammle, and A. Perry
Neuropathology for the Neuroradiologist: Antoni A and Antoni B Tissue Patterns
AJNR Am. J. Neuroradiol., October 1, 2007; 28(9): 1633 - 1638.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
N. M. Warrington, B. M. Woerner, G. C. Daginakatte, B. Dasgupta, A. Perry, D. H. Gutmann, and J. B. Rubin
Spatiotemporal Differences in CXCL12 Expression and Cyclic AMP Underlie the Unique Pattern of Optic Glioma Growth in Neurofibromatosis Type 1
Cancer Res., September 15, 2007; 67(18): 8588 - 8595.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. K. Sandsmark, H. Zhang, B. Hegedus, C. L. Pelletier, J. D. Weber, and D. H. Gutmann
Nucleophosmin Mediates Mammalian Target of Rapamycin-Dependent Actin Cytoskeleton Dynamics and Proliferation in Neurofibromin-Deficient Astrocytes
Cancer Res., May 15, 2007; 67(10): 4790 - 4799.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
G. C. Daginakatte and D. H. Gutmann
Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth
Hum. Mol. Genet., May 1, 2007; 16(9): 1098 - 1112.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
W. F. Khalaf, F.-C. Yang, S. Chen, H. White, W. Bessler, D. A. Ingram, and D. W. Clapp
K-ras Is Critical for Modulating Multiple c-kit-Mediated Cellular Functions in Wild-Type and Nf1+/- Mast Cells
J. Immunol., February 15, 2007; 178(4): 2527 - 2534.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
S. S. Houshmandi, E. I. Surace, H. B. Zhang, G. N. Fuller, and D. H. Gutmann
Tumor suppressor in lung cancer-1 (TSLC1) functions as a glioma tumor suppressor
Neurology, November 28, 2006; 67(10): 1863 - 1866.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
B. Barkan, S. Starinsky, E. Friedman, R. Stein, and Y. Kloog
The Ras Inhibitor Farnesylthiosalicylic Acid as a Potential Therapy for Neurofibromatosis Type 1.
Clin. Cancer Res., September 15, 2006; 12(18): 5533 - 5542.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
B. Dasgupta, Y. Yi, B. Hegedus, J. D. Weber, and D. H. Gutmann
Cerebrospinal Fluid Proteomic Analysis Reveals Dysregulation of Methionine Aminopeptidase-2 Expression in Human and Mouse Neurofibromatosis 1-Associated Glioma
Cancer Res., November 1, 2005; 65(21): 9843 - 9850.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
M. K. Sharma, B. A. Zehnbauer, M. A. Watson, and D. H. Gutmann
RAS pathway activation and an oncogenic RAS mutation in sporadic pilocytic astrocytoma
Neurology, October 25, 2005; 65(8): 1335 - 1336.
[Full Text] [PDF]

Home page
 J. Neurosci.Home page
B. Dasgupta and D. H. Gutmann
Neurofibromin Regulates Neural Stem Cell Proliferation, Survival, and Astroglial Differentiation In Vitro and In Vivo
J. Neurosci., June 8, 2005; 25(23): 5584 - 5594.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
B. Dasgupta, Y. Yi, D. Y. Chen, J. D. Weber, and D. H. Gutmann
Proteomic Analysis Reveals Hyperactivation of the Mammalian Target of Rapamycin Pathway in Neurofibromatosis 1-Associated Human and Mouse Brain Tumors
Cancer Res., April 1, 2005; 65(7): 2755 - 2760.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2005 by the American Association for Cancer Research.