Deletions of AXIN1, a Component of the WNT/wingless Pathway, in Sporadic Medulloblastomas

Advances in Brief

Deletions of AXIN1, a Component of the WNT/wingless Pathway, in Sporadic Medulloblastomas¹

R. P. Dahmen, A. Koch, D. Denkhaus, J. C. Tonn, N. Sörensen, F. Berthold, J. Behrens, W. Birchmeier, O. D. Wiestler and T. Pietsch²

Department of Neuropathology, University of Bonn Medical Center, D-53105 Bonn, Germany [R. P. D., A. K., D. D., O. D. W., T. P.]; Department of Neurosurgery at the Ludwig Maximilian University in Munich, D-81377 Munich, Germany [J. C. T.]; Department of Pediatric Neurosurgery, University of Würzburg, D-97080 Würzburg, Germany [N. S.]; Department of Pediatric Hematology/Oncology, University of Cologne, D-50924 Cologne, Germany [F. B.]; Department of Experimental Medicine II, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany [J. B.]; and Max-Delbrück-Center for Molecular Medicine, D-13092 Berlin, Germany [W. B.]

Medulloblastoma (MB) represents the most frequent malignantbrain tumor in children. Most MBs appear sporadically; however,their incidence is highly elevated in two inherited tumor predispositionsyndromes, Gorlin’s and Turcot’s syndrome. The geneticdefects responsible for these diseases have been identified.Whereas Gorlin’s syndrome patients carry germ-line mutationsin the patched (PTCH) gene, Turcot’s syndrome patientswith MBs carry germ-line mutations of the adenomatous polyposiscoli (APC) gene. The APC gene product is a component of a multiproteincomplex controlling ß-catenin degradation. In thiscomplex, Axin plays a major role as scaffold protein. WhereasAPC mutations are rare in sporadic MBs, a hot-spot region ofß-catenin (CTNNB1) mutations was identified in a subsetof MBs. To find out if Axin is also involved in the pathogenesisof sporadic MBs, we analyzed 86 MBs and 11 MB cell lines formutations in the AXIN1 gene. Using single-strand conformationpolymorphism analysis, screening for large deletions by reversetranscription-PCR, and sequencing analysis, a single somaticpoint mutation in exon 1 (Pro255Ser) and seven large deletions(12%) of AXIN1 were detected. This indicates that AXIN1 mayfunction as a tumor suppressor gene in MBs.

This article has been cited by other articles:

C.-Y. Ou, J. H. Kim, C. K. Yang, and M. R. Stallcup
Requirement of Cell Cycle and Apoptosis Regulator 1 for Target Gene Activation by Wnt and {beta}-Catenin and for Anchorage-independent Growth of Human Colon Carcinoma Cells
J. Biol. Chem., July 31, 2009; 284(31): 20629 - 20637.
[Abstract] [Full Text] [PDF]

T. Chen, M. Li, Y. Ding, L.-s. Zhang, Y. Xi, W.-j. Pan, D.-l. Tao, J.-y. Wang, and L. Li
Identification of Zinc-finger BED Domain-containing 3 (Zbed3) as a Novel Axin-interacting Protein That Activates Wnt/{beta}-Catenin Signaling
J. Biol. Chem., March 13, 2009; 284(11): 6683 - 6689.
[Abstract] [Full Text] [PDF]

J. Huang, M. A. Grotzer, T. Watanabe, E. Hewer, T. Pietsch, S. Rutkowski, and H. Ohgaki
Mutations in the Nijmegen Breakage Syndrome Gene in Medulloblastomas
Clin. Cancer Res., July 1, 2008; 14(13): 4053 - 4058.
[Abstract] [Full Text] [PDF]

J. M. de Bont, R. J. Packer, E. M. Michiels, M. L. d. Boer, and R. Pieters
Biological background of pediatric medulloblastoma and ependymoma: A review from a translational research perspective
Neuro-oncol, January 1, 2008; 10(6): 1040 - 1060.
[Abstract] [Full Text] [PDF]

X. Su, V. Gopalakrishnan, D. Stearns, K. Aldape, F. F. Lang, G. Fuller, E. Snyder, C. G. Eberhart, and S. Majumder
Abnormal Expression of REST/NRSF and Myc in Neural Stem/Progenitor Cells Causes Cerebellar Tumors by Blocking Neuronal Differentiation.
Mol. Cell. Biol., March 1, 2006; 26(5): 1666 - 1678.
[Abstract] [Full Text] [PDF]

S Salahshor and J R Woodgett
The links between axin and carcinogenesis
J. Clin. Pathol., March 1, 2005; 58(3): 225 - 236.
[Abstract] [Full Text] [PDF]

N. S. Fearnhead, J. L. Wilding, B. Winney, S. Tonks, S. Bartlett, D. C. Bicknell, I. P. M. Tomlinson, N. J. McC. Mortensen, and W. F. Bodmer
Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas
PNAS, November 9, 2004; 101(45): 15992 - 15997.
[Abstract] [Full Text] [PDF]

A. R. Hallahan, J. I. Pritchard, S. Hansen, M. Benson, J. Stoeck, B. A. Hatton, T. L. Russell, R. G. Ellenbogen, I. D. Bernstein, P. A. Beachy, et al.
The SmoA1 Mouse Model Reveals That Notch Signaling Is Critical for the Growth and Survival of Sonic Hedgehog-Induced Medulloblastomas
Cancer Res., November 1, 2004; 64(21): 7794 - 7800.
[Abstract] [Full Text] [PDF]

J. Tournoy, X. Bossuyt, A. Snellinx, M. Regent, M. Garmyn, L. Serneels, P. Saftig, K. Craessaerts, B. De Strooper, and D. Hartmann
Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice
Hum. Mol. Genet., July 1, 2004; 13(13): 1321 - 1331.
[Abstract] [Full Text] [PDF]

M A Dyer
Mouse models of childhood cancer of the nervous system
J. Clin. Pathol., June 1, 2004; 57(6): 561 - 576.
[Abstract] [Full Text] [PDF]

V P Collins
Brain tumours: classification and genes
J. Neurol. Neurosurg. Psychiatry, June 1, 2004; 75(suppl_2): ii2 - ii11.
[Full Text] [PDF]

F. Cong and H. Varmus
Nuclear-cytoplasmic shuttling of Axin regulates subcellular localization of {beta}-catenin
PNAS, March 2, 2004; 101(9): 2882 - 2887.
[Abstract] [Full Text] [PDF]

M. Morkel, J. Huelsken, M. Wakamiya, J. Ding, M. van de Wetering, H. Clevers, M. M. Taketo, R. R. Behringer, M. M. Shen, and W. Birchmeier
{beta}-Catenin regulates Cripto- and Wnt3-dependent gene expression programs in mouse axis and mesoderm formation
Development, December 22, 2003; 130(25): 6283 - 6294.
[Abstract] [Full Text] [PDF]

J. A. Morrison, A. J. Klingelhutz, and N. Raab-Traub
Epstein-Barr Virus Latent Membrane Protein 2A Activates {beta}-Catenin Signaling in Epithelial Cells
J. Virol., November 15, 2003; 77(22): 12276 - 12284.
[Abstract] [Full Text] [PDF]

Y. Xing, W. K. Clements, D. Kimelman, and W. Xu
Crystal structure of a {beta}-catenin/Axin complex suggests a mechanism for the {beta}-catenin destruction complex
Genes & Dev., November 15, 2003; 17(22): 2753 - 2764.
[Abstract] [Full Text] [PDF]

A. Caricasole, T. Ferraro, L. Iacovelli, E. Barletta, A. Caruso, D. Melchiorri, G. C. Terstappen, and F. Nicoletti
Functional Characterization of WNT7A Signaling in PC12 Cells: INTERACTION WITH A FZD5{middle dot}LRP6 RECEPTOR COMPLEX AND MODULATION BY DICKKOPF PROTEINS
J. Biol. Chem., September 26, 2003; 278(39): 37024 - 37031.
[Abstract] [Full Text] [PDF]

Y. Lee, H. L. Miller, P. Jensen, R. Hernan, M. Connelly, C. Wetmore, F. Zindy, M. F. Roussel, T. Curran, R. J. Gilbertson, et al.
A Molecular Fingerprint for Medulloblastoma
Cancer Res., September 1, 2003; 63(17): 5428 - 5437.
[Abstract] [Full Text] [PDF]

E. Provost, Y. Yamamoto, I. Lizardi, J. Stern, T. G. D'Aquila, R. B. Gaynor, and D. L. Rimm
Functional Correlates of Mutations in {beta}-Catenin Exon 3 Phosphorylation Sites
J. Biol. Chem., August 22, 2003; 278(34): 31781 - 31789.
[Abstract] [Full Text] [PDF]

R. J. Wechsler-Reya
Analysis of Gene Expression in the Normal and Malignant Cerebellum
Recent Prog. Horm. Res., January 1, 2003; 58(1): 227 - 248.
[Abstract] [Full Text] [PDF]

C. G. Eberhart
Medulloblastoma in Mice Lacking p53 and PARP: All Roads Lead To Gli
Am. J. Pathol., January 1, 2003; 162(1): 7 - 10.
[Full Text] [PDF]

W.-M. Tong, H. Ohgaki, H. Huang, C. Granier, P. Kleihues, and Z.-Q. Wang
Null Mutation of DNA Strand Break-Binding Molecule Poly(ADP-ribose) Polymerase Causes Medulloblastomas in p53-/- Mice
Am. J. Pathol., January 1, 2003; 162(1): 343 - 352.
[Abstract] [Full Text] [PDF]

J. Y. Leung, F. T. Kolligs, R. Wu, Y. Zhai, R. Kuick, S. Hanash, K. R. Cho, and E. R. Fearon
Activation of AXIN2 Expression by beta -Catenin-T Cell Factor. A FEEDBACK REPRESSOR PATHWAY REGULATING Wnt SIGNALING
J. Biol. Chem., June 7, 2002; 277(24): 21657 - 21665.
[Abstract] [Full Text] [PDF]