The G protein α subunit Gαs is a tumor suppressor in Sonic hedgehog-driven medulloblastoma

Nature Medicine

Volumn 20, Issue 9, 2014, Pages 1035-1042

  He, Xuelian ^a   Zhang, Liguo ^b   Chen, Ying ^b,c   Remke, Marc ^d   Shih, David ^d   Lu, Fanghui ^b   Wang, Haibo ^b   Deng, Yaqi ^b   Yu, Yang ^a   Xia, Yong ^e   Wu, Xiaochong ^d   Ramaswamy, Vijay ^d   Hu, Tom ^f   Wang, Fan ^a   Zhou, Wenhao ^g   Burns, Dennis K ^f   Kim, Se Hoon ^h   Kool, Marcel ⁱ   Pfister, Stefan M ⁱ   Weinstein, Lee S ^j   Pomeroy, Scott L ^k   Gilbertson, Richard J ^l   Rubin, Joshua B ^m   Hou, Yiping ^a   Wechsler Reya, Robert ⁿ   Taylor, Michael D ^d   Lu, Q Richard ^a,b,g   more..

^a SICHUAN UNIVERSITY   (China)

^b Division of Experimental Hematology and Cancer Biology   (United States)

^c XIAMEN UNIVERSITY   (China)

^d HOSPITAL FOR SICK CHILDREN   (Canada)

^e SICHUAN UNIVERSITY   (China)

^f UNIVERSITY OF TEXAS AT DALLAS   (United States)

^g FUDAN UNIVERSITY   (China)

^h Yonsei University College of Medicine   (South Korea)

ⁱ GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

^j NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES   (United States)

^k BOSTON CHILDREN S HOSPITAL   (United States)

^l ST JUDE CHILDREN S RESEARCH HOSPITAL   (United States)

^m WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

ⁿ BURNHAM INSTITUTE   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIC AMP; CYCLIN D1; GUANINE NUCLEOTIDE BINDING PROTEIN ALPHA SUBUNIT; MESSENGER RNA; MYC PROTEIN; PHOSPHODIESTERASE IV; PROTEIN PATCHED 1; ROLIPRAM; SMOOTHENED PROTEIN; SONIC HEDGEHOG PROTEIN; TRANSCRIPTION FACTOR GLI1; TRANSCRIPTION FACTOR GLI2; TRANSCRIPTOME; VISMODEGIB; STIMULATORY GUANINE NUCLEOTIDE BINDING PROTEIN;

ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; BLOOD BRAIN BARRIER; CANCER GROWTH; CANCER SURVIVAL; CELL GRANULE; CELL LINEAGE; CELL MIGRATION; CELL PROLIFERATION; CILIARY MOTILITY; COCHLEAR NUCLEUS; CONTROLLED STUDY; DRUG EFFICACY; DRUG TOLERABILITY; EMBRYO; ENZYME ACTIVITY; EUKARYOTIC FLAGELLUM; FEMALE; FIBROBLAST; FRAMESHIFT MUTATION; GAIN OF FUNCTION MUTATION; GENE; GENE EXPRESSION; GENE EXPRESSION PROFILING; GENETIC ASSOCIATION; GNAS GENE; HUMAN; HUMAN CELL; IN SITU HYBRIDIZATION; KNOCKOUT MOUSE; LOSS OF FUNCTION MUTATION; MALE; MEDULLOBLASTOMA; MOUSE; NEWBORN; NONHUMAN; NONSENSE MUTATION; OVERALL SURVIVAL; PRECURSOR; PRIORITY JOURNAL; PROTEIN DEGRADATION; QUANTITATIVE ANALYSIS; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RNA ISOLATION; SIGNAL TRANSDUCTION; UPREGULATION; WILD TYPE; YOUNG ADULT; BRAIN TUMOR; GENETICS; METABOLISM; NEURAL STEM CELL;

ERINACEIDAE; MUS;

BRAIN NEOPLASMS; CYCLIC AMP; GTP-BINDING PROTEIN ALPHA SUBUNITS, GS; HEDGEHOG PROTEINS; HUMANS; MEDULLOBLASTOMA; NEURAL STEM CELLS; SIGNAL TRANSDUCTION;

EID: 84908343987     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.3666     Document Type: Article

References (60)

1. Taylor, M.D. et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 123, 465-472 (2012).
2. Northcott, P.A. et al. Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct. Acta Neuropathol. 122, 231-240 (2011).
3. Grammel, D. et al. Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem. Acta Neuropathol. 123, 601-614 (2012).
4. Sasai, K. et al. Medulloblastomas derived from Cxcr6 mutant mice respond to treatment with a smoothened inhibitor. Cancer Res. 67, 3871-3877 (2007).
5. Kool, M. et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to Smoothened inhibition. Cancer Cell 25, 393-405 (2014).
6. Niewiadomski, P., Zhujiang, A., Youssef, M. & Waschek, J.A. Interaction of PACAP with Sonic hedgehog reveals complex regulation of the hedgehog pathway by PKA. Cell. Signal. 25, 2222-2230 (2013).
7. Neves, S.R., Ram, P.T. & Iyengar, R. G protein pathways. Science 296, 1636-1639 (2002).
8. Kan, Z. et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466, 869-873 (2010).
9. Huh, J.Y. et al. Novel nonsense GNAS mutation in a 14-month-old boy with plate-like osteoma cutis and medulloblastoma. J. Dermatol. 41, 319-321 (2014).
10. Cho, Y.J. et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J. Clin. Oncol. 29, 1424-1430 (2011).
11. Remke, M. et al. Adult medulloblastoma comprises three major molecular variants. J. Clin. Oncol. 29, 2717-2723 (2011).
12. Remke, M. et al. FSTL5 is a marker of poor prognosis in non-WNT/non-SHH medulloblastoma. J. Clin. Oncol. 29, 3852-3861 (2011).
13. Yang, Z.J. et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 14, 135-145 (2008).
14. Zhuo, L. et al. hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis 31, 85-94 (2001).
15. Northcott, P.A., Korshunov, A., Pfister, S.M. & Taylor, M.D. The clinical implications of medulloblastoma subgroups. Nat. Rev. Neurol. 8, 340-351 (2012).
16. Regard, J.B. et al. Wnt/β-catenin signaling is differentially regulated by Gα proteins and contributes to fibrous dysplasia. Proc. Natl. Acad. Sci. USA 108, 20101-20106 (2011).
17. Lu, Q.R. et al. Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell 109, 75-86 (2002).
18. Hohenegger, M. et al. Gsα-selective G protein antagonists. Proc. Natl. Acad. Sci. USA 95, 346-351 (1998).
19. Graziano, M.P. & Gilman, A.G. Synthesis in Escherichia coli of GTPase-deficient mutants of Gs alpha. J. Biol. Chem. 264, 15475-15482 (1989).
20. Dorsam, R.T. & Gutkind, J.S. G-protein-coupled receptors and cancer. Nat. Rev. Cancer 7, 79-94 (2007).
21. Tuson, M., He, M. & Anderson, K.V. Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube. Development 138, 4921-4930 (2011).
22. Nozawa, Y.I., Lin, C. & Chuang, P.T. Hedgehog signaling from the primary cilium to the nucleus: an emerging picture of ciliary localization, trafficking and transduction. Curr. Opin. Genet. Dev. 23, 429-437 (2013).
23. Pan, Y., Wang, C. & Wang, B. Phosphorylation of Gli2 by protein kinase A is required for Gli2 processing and degradation and the Sonic Hedgehog-regulated mouse development. Dev. Biol. 326, 177-189 (2009).
24. Nikulina, E., Tidwell, J.L., Dai, H.N., Bregman, B.S. & Filbin, M.T. The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. Proc. Natl. Acad. Sci. USA 101, 8786-8790 (2004).
25. Conti, M. & Jin, S.L. The molecular biology of cyclic nucleotide phosphodiesterases. Prog. Nucleic Acid Res. Mol. Biol. 63, 1-38 (1999).
26. Wang, B., Fallon, J.F. & Beachy, P.A. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100, 423-434 (2000).
27. Ruiz i Altaba, A., Mas, C. & Stecca, B. The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol. 17, 438-447 (2007).
28. Regard, J.B. et al. Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification. Nat. Med. 19, 1505-1512 (2013).
29. Mukhopadhyay, S. et al. The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling. Cell 152, 210-223 (2013).
30. Yang, L. et al. Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo. Cancer Res. 67, 651-658 (2007).
31. Rohatgi, R., Milenkovic, L. & Scott, M.P. Patched1 regulates hedgehog signaling at the primary cilium. Science 317, 372-376 (2007).
32. Goetz, S.C., Ocbina, P.J. & Anderson, K.V. The primary cilium as a Hedgehog signal transduction machine. Methods Cell Biol. 94, 199-222 (2009).
33. Chen, J.K., Taipale, J., Young, K.E., Maiti, T. & Beachy, P.A. Small molecule modulation of Smoothened activity. Proc. Natl. Acad. Sci. USA 99, 14071-14076 (2002).
34. Dijkgraaf, G.J. et al. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res. 71, 435-444 (2011).
35. Schüller, U. et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 14, 123-134 (2008).
36. Xin, M. et al. Myelinogenesis and axonal recognition by oligodendrocytes in brain are uncoupled in Olig1-null mice. J. Neurosci. 25, 1354-1365 (2005).
37. Lu, Q.R. et al. Sonic hedgehog-regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron 25, 317-329 (2000).
38. Machold, R., Klein, C. & Fishell, G. Genes expressed in Atoh1 neuronal lineages arising from the r1/isthmus rhombic lip. Gene Expr. Patterns 11, 349-359 (2011).
39. Gibson, P. et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 468, 1095-1099 (2010).
40. Gilbertson, R.J. & Ellison, D.W. The origins of medulloblastoma subtypes. Annu. Rev. Pathol. 3, 341-365 (2008).
41. Pounds, S. et al. A procedure to statistically evaluate agreement of differential expression for cross-species genomics. Bioinformatics 27, 2098-2103 (2011).
42. Tibshirani, R., Hastie, T., Narasimhan, B. & Chu, G. Diagnosis of multiple cancer types by shrunken centroids of gene expression. Proc. Natl. Acad. Sci. USA 99, 6567-6572 (2002).
43. Sengupta, R. et al. CXCR4 activation defines a new subgroup of Sonic hedgehog-driven medulloblastoma. Cancer Res. 72, 122-132 (2012).
44. Northcott, P.A. et al. Subgroup-specific structural variation across 1, 000 medulloblastoma genomes. Nature 488, 49-56 (2012).
45. Mishra, P.K. et al. Misregulation of Scm3p/HJURP causes chromosome instability in Saccharomyces cerevisiae and human cells. PLoS Genet. 7, e1002303 (2011).
46. Dunleavy, E.M. et al. HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A at centromeres. Cell 137, 485-497 (2009).
47. Parsons, D.W. et al. The genetic landscape of the childhood cancer medulloblastoma. Science 331, 435-439 (2011).
48. Silbereis, J.C. et al. Olig1 function is required to repress dlx1/2 and interneuron production in Mammalian brain. Neuron 81, 574-587 (2014).
49. O'Hayre, M. et al. The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer. Nat. Rev. Cancer 13, 412-424 (2013).
50. Romer, J.T. et al. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1+/? p53?/? mice. Cancer Cell 6, 229-240 (2004).
51. Yauch, R.L. et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326, 572-574 (2009).
52. Sengupta, R., Sun, T., Warrington, N.M. & Rubin, J.B. Treating brain tumors with PDE4 inhibitors. Trends Pharmacol. Sci. 32, 337-344 (2011).
53. Chahar, M.K., Sharma, N., Dobhal, M.P. & Joshi, Y.C. Flavonoids: A versatile source of anticancer drugs. Pharmacogn. Rev. 5, 1-12 (2011).
54. Nikaido, T. et al. Inhibition of adenosine 3′, 5′-cyclic monophosphate phosphodiesterase by flavonoids. III. Chem. Pharm. Bull. (Tokyo) 37, 1392-1395 (1989).
55. Ng, J.M. & Curran, T. The Hedgehog's tale: developing strategies for targeting cancer. Nat. Rev. Cancer 11, 493-501 (2011).
56. Chen, M. et al. Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gsα deficiency. J. Clin. Invest. 115, 3217-3227 (2005).
57. Northcott, P.A. et al. Medulloblastoma comprises four distinct molecular variants. J. Clin. Oncol. 29, 1408-1414 (2011).
58. Northcott, P.A. et al. Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples. Acta Neuropathol. 123, 615-626 (2012).
59. Carvalho, B.S. & Irizarry, R.A. A framework for oligonucleotide microarray preprocessing. Bioinformatics 26, 2363-2367 (2010).
60. Vilella, A.J. et al. EnsemblCompara GeneTrees: Complete, duplication-aware phylogenetic trees in vertebrates. Genome Res. 19, 327-335 (2009).