THE TUMOR SUPPRESSOR GENE PTEN/MMAC1 SIGNALING IN BRAIN TUMORS

Biochemical and Cellular Archives

Volumn 11, Issue 1, 2011, Pages 1-18

  Kumar, Birendra ^a,b   Moshahid, M ^a   Rizvi, A ^a   Yadav, P R ^b  

^a JAMIA MILLIA ISLAMIA CENTRAL UNIVERSITY   (India)

^b DAV College Muzaffarnagar   (India)

Author keywords

brain; glioblastoma; PI3 kinase; PTEN; tumor suppressor

Indexed keywords

EID: 84555188369     PISSN: 09725075     EISSN: 09761772     Source Type: Journal    
DOI: None     Document Type: Article

References (175)

1. Abel T W, Baker S J, Fraser M M, Tihan T, Nelson J S and Yachnis A T (2005) Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway. J. Neuropathol. Exp. Neuro. 64, 341–349.
2. Agochiya M, Brunton V G, Owens D W, Parkinson E K, Paraskeva C, Keith W N and Frame M C (1999) Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells. Oncogene 18, 5646-5653.
3. Asada M, Yamada T, Ichijo H, Delia D, Miyazono K, Fukumuro K and Mizutani S (1999) Apoptosis inhibitory activity of cytoplasmic p21(Cip1/WAF1) in monocytic differentiation. EMBO J. 18, 1223-1234.
4. Backman S A, Stambolic V, Suzuki A, Haight J, Elia A and Pretorius J (2001) Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease. Nat Genet. 29, 396–403.
5. Baeza N, Weller M, Yonekawa Y, Kleihues P and Ohgaki H (2003) PTEN methylation and expression in glioblastomas. Acta Neuropathol. 106, 479–485.
6. Bao S, Wu Q, McLendon R E, Hao Y, Shi Q and Hjelmel and A B (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760.
7. Bellacosa A, de Feo D, Godwin A K, Bell D W, Cheng J Q, Altomare D A (1995) Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int. J. Cancer 64, 280–285.
8. Bianco R, Shin I, Ritter CA, Yakes FM, Basso A and Rosen N (2003) Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 22, 2812–2822.
9. Bigner S H and Vogelstein B (1990) Cytogenetics and molecular genetics of malignant gliomas and medulloblastoma. Brain Pathol. 1, 12– 18.
10. Bjornsti M A and Houghton P J (2004) The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4, 335–348.
11. Blancher C, Moore J W, Robertson N and Harris A L (2001) Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1a, HIF-2a, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3’-kinase/Akt signaling pathway. Cancer Res. 61, 7349-7355.
12. Boland E, Clayton-Smith J, Woo V G, McKee S, Manson F D and Medne L (2007) Mapping of deletion and translocation break points in 1q44 implicates the serine/threonine kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum. Am. J. Hum. Genet. 81, 292–303.
13. Boström J, Cobbers J M J L, Wolter M, Tabatabai G, Weber R G, Lichter P, Collins V P and Reifenberger G (1998) Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q. Cancer Res. 58, 29-33.
14. Broderick D K, Di C, Parrett T J, Samuels Y R, Cummins J M and McLendon R E (2004) Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas. Cancer Res. 64, 5048–5050.
15. Butler M G, Dasouki M J, Zhou X P, Talebizadeh Z, Brown M and Takahashi T N (2005) Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J. Med Genet. 42, 318–321.
16. Chakravarti A, Delaney M A, Noll E, Black P M, Loeffler J S and Muzikansky A (2001) Prognostic and pathologic significance of quantitative protein expression profiling in human gliomas. Clin. Cancer Res.7, 2387–2395.
17. Chang C J, Freeman D J and Wu H (2004) PTEN regulates Mdm2 expression through the P1 promoter. J. biol. Chem. 279, 29841– 29848.
18. Chen M L, Xu P Z, Peng X D, Chen W S, Guzman G and Yang X (2006) The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/_ mice. Genes Dev. 20, 1569–1574.
19. Chen Z, Trotman L C, Shaffer D, Lin H K, Dotan Z A and Niki M (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725– 730.
20. Cheng J Q and Nicosia S V (2001) AKT signal transduction pathway in oncogenesis Schwab Deds. Encyc Ref Cancer 35-37.
21. Cheng J Q, Ruggeri B, Klein W M, Sonoda G, Altomare D A, Watson D K and Testa J R (1996) Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc. Natl. Acad. Sci. U.S.A. 93, 3636-3641.
22. Cheng JQ, Altomare DA, Klein MA, Lee WC, Kruh GD, Lissy NA and Testa J R (1997) Transforming activity and cell cycle-dependent expression of the AKT2 oncogene: evidence for a link between cell cycle regulation and oncogenesis. Oncogene14, 2793-2801.
23. Cheney I W, Johnson D E, Vaillancourt M T, Avanzini J, Morimoto A, Demers G W, Wills K N, Shabram P W, Bolen J B, Tavtigian S V and Bookstein R (1998) Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer. Cancer Res. 58, 2331-2334.
24. Cheney I W, Neuteboom S T, Vaillancourt M T, Ramachandra M and Bookstein R (1999) Adenovirus-mediated gene transfer of MMAC1/PTEN to glioblastoma cells inhibits S phase entry by the recruitment of p27Kip1 into cyclin E/CDK2 complexes. Cancer Res. 59, 2318-2323.
25. Cheng J Q, Godwin A K, Bellacosa A, Taguchi T, Franke T F, Hamilton T C, Tsichlis P N and Testa J R (1992) AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc. Natl. Acad. Sci. U.S.A. 89, 9267-9271.
26. Chiariello E, Roz L, Albarosa R, Magnani I and Finocchiaro G (1998) PTEN/MMAC1 mutations in primary glioblastomas and short-term cultures of malignant gliomas. Oncogene 16, 541-545.
27. Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J and Zhu S (2008) Antitumor activity of rapamycin in a phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 5, e8.
28. Datta S R, Brunet A and Greenberg M E (1999) Cellular survival: a play in three Akt. Genes Dev. 13, 2905-2927.
29. Davies M P, Gibbs F E, Halliwell N, Joyce K A, Roebuck M M, Rossi M L, Salisbury J, Sibson D R, Tacconi L and Walker C (1999) Mutation in the PTEN/MMAC1 gene in archival low grade and high grade gliomas. Br. J. Cancer 79, 1542-1548.
30. Davies M A, Lu Y, Sano T, Fang X, Tang P, LaPushin R, Koul D, Bookstein R, Stokoe D, Yung W K, Mills G B and Steck P A (1998) Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis. Cancer Res. 58, 5285-5290.
31. Ding H, Roncari L, Shannon P, Wu X, Lau N and Karaskova J (2001) Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Cancer Res. 61, 3826–3836.
32. Duerr E M, Rollbrocker B, Hayashi Y, Peters N, Meyer-Puttlitz B, Louis D N, Schramm J, Wiestler O D, Parsons R, Eng C and von Deimling A (1998) PTEN mutations in gliomas and glioneuronal tumors. Oncogene 16, 2259-2264.
33. Easton R M, Cho H, Roovers K, Shineman D W, Mizrahi M and FormanM S (2005) Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol Cell Biol. 25, 1869–1878.
34. Ebert C, von Haken M, Meyer-Puttlitz B, Wiestler O D, Reifenberger G, Pietsch T and von Deimling A (1999) Molecular genetic analysis of ependymal tumors: NF2 mutations and chromosome 22q loss occur preferentially in intramedullary spinal ependymomas. Am. J. Pathol. 155, 627-632.
35. Eng C (2003) PTEN: one gene, many syndromes. Hum. Mutat. 22, 183–198.
36. Fan Q W, Cheng C K, Nicolaides T P, Hackett C S, Knight Z A and Shokat K M (2007) A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTENmutant glioma. Cancer Res.67, 7960– 7965.
37. Fan Q W, Knight Z A, Goldenberg D D, Yu W, Mostov K E and Stokoe D (2006) A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9, 341–349.
38. Fraser M M, Bayazitov I T, Zakharenko S S and Baker S J (2008) Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities. Neuroscience 151, 476–488.
39. Fraser M M, Zhu X, Kwon C H, Uhlmann E J, Gutmann D H and Baker S J (2004) Pten loss causes hypertrophy and increased proliferation of astrocytes in vivo. Cancer Res. 64, 7773–7779.
40. Freeman DJ, Li AG, Wei G, Li HH, Kertesz N and Lesche R (2003) PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell 3, 117–130.
41. Furnari F B, Lin H, Huang H S and CaveneeW K (1997) Growth suppression of glioma cells by Pten requires a functional phosphatase catalytic domain. Proc. Natl. Acad. Sci. U.S.A. 94, 12479-12484.
42. Furnari F B, Huang H J S and Cavenee W K (1998) The phosphoinositol phosphatase activity of Pten mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer Res. 58, 5002-5008.
43. Fuse T, Tanikawa M, Nakanishi M, Ikeda K, Tada T, Inagaki H, Asai K, Kato T and Yamada K (2000) p27Kip1 expression by contact inhibition as a prognostic index of human glioma. J. Neurochem. 74, 1393-1399.
44. Georgescu M M, Kirsch K H, Akagi T, Shishido T and Hanafusa H (1999) The tumor-suppressor activity of PTEN is regulated by its carboxylterminal region. Proc. Natl. Acad. Sci. U.S.A. 96, 10182-10187.
45. Giri D and Ittmann M (1999) Inactivation of the PTEN tumor suppressor gene is associated with increased angiogenesis in clinically localized prostate carcinoma. Hum. Pathol. 30, 419-424.
46. Goffin A, Hoefsloot L H, Bosgoed E, Swillen A and Fryns J P (2001) PTEN mutation in a family with Cowden syndrome and autism. Am. J. Med. Genet. 105, 521–524.
47. Gottschalk A R, Basila D, Wong M, Dean N M, Brandts C H, Stokoe D and Haas-Kogan D A (2001) p27Kip1 is required for Pten-induced G1 growth arrest. Cancer Res. 61, 2105-2111.
48. Goudar R K, Shi Q, Hjelmel and M D, Keir S T, McLendon R E and Wikstrand C J (2005) Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. Mol Cancer Ther. 4, 101–112.
49. Groszer M, Erickson R, Scripture-Adams D D, Dougherty J D, Le Belle J and Zack J A (2006) PTEN negatively regulates neural stem cell self-renewal by modulating G0-G1 cell cycle entry. Proc Natl Acad Sci USA 103, 111–116.
50. Groszer M, Erickson R, Scripture-Adams DD, Lesche R, Trumpp A and Zack J A (2001) Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294, 2186–2189.
51. Gustafson S, Zbuk K M, Scacheri C and Eng C (2007) Cowden syndrome. Semin Oncol. 34, 428–434.
52. He J, Mokhtari K, Sanson M, Marie Y, Kujas M, Huguet S, Leuraud P, Capelle L, Delattre J Y, Poirier J and Hoang-Xuan K (2001) Glioblastomas with an oligodendroglial component: A pathological and molecular study. J. Neuropathol. Exp. Neurol. 60, 863-871.
53. Holland E C (2000) Glioblastoma multiforme: the terminator. Proc. Natl. Acad. Sci. USA 97, 6242-6244.
54. Holland E C, Celestino J, Dai C, Schaefer L, Sawaya R E and Fuller G N (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat. Genet. 25, 55-57.
55. Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi PP, Manova-Todorova K and Holland E C (2008) PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev. 22, 436–448.
56. Hartmann C, Bartels G, Gehlhaar C, Holtkamp N, von Deimling A. (2005a) PIK3CA mutations in glioblastoma multiforme. Acta Neuropathol. 109, 639–642.
57. Hartmann W, Koch A, Brune H, Waha A, Schuller U and Dani I (2005b) Insulin-like growth factor II is involved in the proliferation control of medulloblastoma and its cerebellar precursor cells. Am J Pathol. 166, 1153–1162.
58. Hartmann W, Digon-Sontgerath B, Koch A, Waha A, Endl E and Dani I (2006) Phosphatidylinositol 30-kinase/AKT signaling is activated in medulloblastoma cell proliferation and is associated with reduced expression of PTEN. Clin Cancer Res. 12, 3019– 3027.
59. Hayes M P, Wang H, Espinal-Witter R, Douglas W, Solomon G J and Baker S J (2006) PIK3CA and PTEN mutations in uterine endometrioid carcinoma and complex atypical hyperplasia. Clin Cancer Res. 12, 5932–5935.
60. Hu X, Pandolfi PP, Li Y, Koutcher JA, Rosenblum M and Holland E C (2005) mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. Neoplasia 7, 356–368.
61. Hunter C, Smith R, Cahill D P, Stephens P, Stevens C and Teague J (2006) A hypermutation phenotype and somaticMSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res. 66, 3987–3991.
62. Iida S, Tanaka Y, Fujii H, Hayashi S, Kimura M and Nagareda T (1998) A heterozygous frameshift mutation of the PTEN/MMAC1 gene in a patient with Lhermitte-Duclos disease— only the mutated allele was expressed in the cerebellar tumor. Int. J. Mol. Med. 1,925–929.
63. Jiang B H, Jiang G, Zheng J Z, Lu Z, Hunter T and Vogt P K (2001) Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ. 12, 363-369.
64. Jones G, Machado J Jr, Tolnay M and Merlo A (2001a) Ptenindependent induction of caspase-mediated cell death and reduced invasion by the focal adhesion targeting domain (FAT) in human astrocytic brain tumors which highly express focal adhesion kinase (FAK). CancerRes. 61, 5688-5691.
65. Jones G, Machado J Jr and Merlo A (2001b) Loss of focal adhesion kinase (FAK) inhibits epidermal growth factor receptor-dependent migration and induces aggregation of nh (2)-terminal FAK in the nuclei of apoptotic glioblastoma cells. Cancer Res. 61, 4978-4981.
66. Kato H, Kato S, Kumabe T, Sonoda Y, Yoshimoto T, Kato S, Han S Y, Suzuki T, Shibata H, Kanamaru R and Ishioka C (2000) Functional evaluation of p53 and PTEN gene mutations in gliomas. Clin. Cancer Res. 6, 3937-3943.
67. Knobbe CB and Reifenberger G (2003) Geneticalterations and aberrant expression of genes related to the phosphatidyl-inositol-30-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Brain Pathol. 13, 507–518.
68. Knobbe C B and Reifenberger G (2001) Molecular genetic analysis of human glioblastomas for aberrations of genes encoding members of the Pten/PI3K/Akt signal transduction pathway. Neuro-Oncology [serial online], Doc. A153, September 24, 2001. URL . Neuro-Oncology 3, 304.
69. Kolibaba K S and Druker B J (1997) Protein tyrosine kinases and cancer. Biochem Biophys Acta 1331, F217-F248.
70. Kotelevets L, van Hengel J, Bruyneel E, Mareel M, van Roy F, and Chastre E (2001) The lipid phosphatase activity of Pten is critical for stabilizingintercellular junctions and reverting invasiveness. J. Cell Biol. 155, 1129-1135.
71. Koul D, Parthasarathy R, Shen R, Davies M A, Jasser S A, Chintala S K, Rao J S, Sun Y, Benvenisite E N, Liu T J and Yung W K (2001) Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN. Oncogene 20, 6669-6678.
72. Kraus J A, Lamszus K, Glesmann N, Beck M, Wolter M, Sabel M, Krex D, Klockgether T, Reifenberger G and Schlegel U (2001) Molecular genetic alterations in glioblastomas with oligodendroglial component. Acta Neuropathol. 101, 311-320.
73. Kwon C H, Luikart B W, Powell C M, Zhou J, Matheny S A and Zhang W (2006) Pten regulates neuronal arborization and social interaction in mice. Neuron 50, 377–388.
74. Kwon C H, Zhu X, Zhang J, Knoop L L, Tharp R and Smeyne R J (2001) Pten regulates neuronal soma size: a mouse model of Lhermitte-Duclos disease. Nat Genet. 29, 404–411.
75. Kubiatowski T, Jang T, Lachyankar M B, Salmonsen R, Nabi R R, Quesenberry P J, Litofsky N S, Ross A H and Recht L D (2001) Association of increased phosphatidylinositol 3-kinase signaling with increased invasiveness and gelatinase activity in malignant gliomas. J. Neurosurg. 95, 480-488.
76. Lachlan KL, Lucassen AM, Bunyan D and Temple I K (2007) Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers. J Med Genet. 44, 579–585.
77. Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q and Donin N M (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9, 391–403.
78. Lee J O, Yang H, Georgescu M M, Di Cristofano A, Maehama T, Shi Y, Dixon J E, Pandol P and Pavletich N P (1999) Crystal structure of the Pten tumor suppressor: Implications for its phosphoinositide phosphatase activity and membrane association. Cell 99, 323-334.
79. Li L, Liu F, Salmonsen R A, Turner T K, Litofsky N S and Di Cristofano A (2002) PTEN in neural precursor cells: regulation of migration, apoptosis, and proliferation. Mol. Cell Neurosci 20, 21–29.
80. Li D M and Sun H (1998) Pten/MMAC1/Tep1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc.Natl. Acad. Sci. U.S.A. 95, 15406-15411.
81. Li D M and Sun H (1997) TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res. 57, 2124–2129.
82. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmannn M, Tycko B, Hibshoosh H, Wigler M H and Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943– 1947.
83. Liaw D, Marsh DJ, Li J, Dahia PLM, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C and Parsons R (1997) Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat. Genet. 16, 64–67.
84. Liliental J, Moon S Y, Lesche R, Mamillapalli R, Li D, Zheng Y, Sun H and Wu H (2000) Genetic deletion of the Pten tumor suppressor gene promotes cell motility by activation of Rac1 and Cdc42 GTPases. Curr. Biol. 10, 401-404.
85. Liu W, James C D, Frederick L, Alderete B E and Jenkins R B (1997) PTEN/MMAC1 mutations and EGFR ampli.cation in glioblastomas. CancerRes. 57, 5254-5257.
86. Louis D N, Ohgaki H, Wiestler O D and Cavenee W K (2007) WHO Classification of Tumours of the Central Nervous System. Internationa Agency for Research on Cancer: Lyon.
87. Lynch ED, Ostermeyer EA, Lee MK, Arena JF, Ji H, Dann J, Swisshelm K, Suchard D, MacLeod PM, Kvinnsland S, Gjertsen BT, Heimdal K, Lubs H, Møller P and King M C (1997) Inherited mutations in PTEN that are associated with breast cancer, Cowden syndrome, and juvenile polyposis. Am. J. Hum. Genet. 61, 1254– 1260.
88. Ma Y Y, Wei S J, Lin Y C, Lung J C, Chang T C, Whang-Peng J, Liu J M, Yang D M, Yang W K and Shen C Y (2000) PIK3CA as an oncogene in cervical cancer. Oncogene 19, 2739-2744.
89. Maehama T, Taylor G S and Dixon J E (2001) Pten and myotubularin: Novel phosphoinositide phophatases. Annu. Rev. Biochem. 70, 247-279.
90. Maehama T and Dixon J E (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. biol. Chem. 273, 13375-13378.
91. Maher E A, Furnari F B, Bachoo R M, Rowitch D H, Louis D N, Cavenee W K and DePinho R A (2001) Malignant glioma: genetics and biology of a grave matter. Genes Dev. 15, 311-333.
92. Maier D, Jones G, Li X, Schonthal A H, Gratzl O, Van Meir E G and Merlo A (1999) The Pten lipid phosphatase domain is not required to inhibit invasion of glioma cells. Cancer Res. 59, 5479-5482.
93. Maier D, Zhang Z, Taylor E, Hamou M F, Gratzl O, Van Meir E G, Scott R J and Merlo A (1998) Somatic deletion mapping on chromosome 10 and sequence analysis of PTEN/MMAC1 point to the 10q25-26 region as the primary target in low-grade and high-grade gliomas. Oncogene 16, 3331-3335.
94. Maity A, Pore N, Haas-Kogan D A and O’Rourke D M (2001) PTEN mutation cooperates with EGFR activation in human glioblastoma cells to increase VEGF mRNA levels by transactivating an element in the proximal promoter. Int. J. Radiat. Oncol. Biol. Phys. 51 (Suppl. 1), 101-102.
95. Maity A, Pore N, Lee J, Solomon D and O’Rourke D M (2000) Epidermal growth factor receptor transcriptionally up-regulates vascular endothelial growth factor expression in human glioblastoma cells via a pathway involving phosphatidylinositol 3’-kinase and distinct from that induced by hypoxia. Cancer Res. 60, 5879-5886.
96. Malmer B, Gronberg H, Andersson U, Jonsson B A and Henriksson R (2001) Microsatellite instability, PTEN and p53germline mutations in glioma families. Acta Oncol.40, 633-637.
97. Mamillapalli R, Gavrilova N, Mihaylova V T, Tsvetkov L M, Wu H, Zhang H and Sun H (2001) Pten regulates the ubiquitin-dependent degradation of the CDK inhibitor p27(KIP1) through the ubiquitin E3 ligase SCF (SKP2). Curr. Biol. 11, 263-267.
98. Marino S, Krimpenfort P, Leung C, van der Korput H A, Trapman J and Camenisch I (2002) PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum. Development 129, 3513–3522.
99. Maroulakou I G, Oemler W, Naber S P and Tsichlis P N (2007) Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenicmice. Cancer Res. 67, 167–177.
100. Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PLM, Zheng Z and Liaw D (1998b) Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan- Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum. Mol. Genet.7, 507–515.
101. Mayo L D, Dixon J E, Durden D L, Tonks N K and Donner D B (2002) PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J. biol. Chem. 277, 5484–5489.
102. Medema R H, Kops G J, Bos J L and Burgering B M (2000) AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782-787.
103. Mellinghoff I K, Wang M Y, Vivanco I, Haas-Kogan D A, Zhu S and Dia E Q (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N. Engl. J. Med. 353, 2012–2024.
104. Myers M P, Stolarov J P, Eng C, Li J, Wang S I and Wigler M H (1997) PTEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci USA 94, 9052–9057.
105. Nagata Y, Lan K H, Zhou X, Tan M, Esteva F J and Sahin A A (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6, 117–127.
106. Nakamura N, Ramaswamy S, Vazquez F, Signoretti S, Loda M and Sellers W R (2000) Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of Pten. Mol. Cell. Biol. 20, 8969-8982.
107. Nakayama K, Nakayama N, Kurman R J, Cope L, Pohl G and Samuels Y (2006) Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms. Cancer Biol Ther. 5, 779–785.
108. Nelen M R, Kremer H, Konings I B M, Schoute F, van Essen A J, Koch R, Woods C G, Fryns J-P, Hamel B, Hoefsloot L H, Peeters E A J and Padberg G W (1999) Novel PTEN mutations in patients with Cowden disease: absence of clear genotypephenotype correlations. Eur. J. Hum. Genet. 7, 267– 273.
109. Nelen M R, van Staveren C G, Peeters E A J, Ben Hassel M, Gorlin RJ, Hamm H, Lindboe C F, Fryns J P, Sijmons R H, Woods D G, Mariman E C M, Padberg G W and Kremer H (1997) Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum. Mol. Genet. 6, 1383–1387.
110. Nelen MR, Padberg GW, Peeters EAJ, Lin AY, van den HelmB, Frants RR, Coulon V, Goldstein AM, van Reen MMM,Easton DF, Eeles RA, Hodgson S, Mulvihill JJ, Murday VA,Tucker MA, Mariman ECM, Starink TM, Ponder BAJ, RopersHH, Kremer H, Longy M and Eng C (1996) Localizationof the gene for Cowden disease to 10q22-23. Nat. Genet.13,114–116
111. Oda K, Stokoe D, Taketani Y and McCormick F (2005) High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res. 65, 10669–10673.
112. Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T and Di Patre P L (2004) Geneticpathways to glioblastoma: a population-based study. Cancer Res. 64, 6892–6899.
113. O’Reilly K E, Rojo F, She Q B, Solit D, Mills G B and Smith D (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 1500–1508.
114. Paramio J M, Navarro M, Segrelles C, Gomez-Casero E and Jorcano J L (1999) Pten tumor suppressor is linked to the cell cycle control through the retinoblastoma protein. Oncogene 18, 7462-7468.
115. Pedrero J M, Carracedo D G, Pinto C M, Zapatero A H, Rodrigo J P and Nieto C S (2005) Frequent geneticand biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma. Int. J. Cancer 114, 242–248.
116. Peraud A, Watanabe K, Schwechheimer K, YonekawaY, Kleihues P and Ohgaki H (1999) Genetic pro.le of the giant cell glioblastoma. Lab. Invest. 79, 123-129.
117. Piva R, Cavalla P, Bortolotto S, Cordera S, Richiardi P and Schiffer D (1997) p27/kip1 expression in human astrocytic gliomas. Neurosci. Lett. 234, 127-130.
118. Prados MD, Lamborn KR, Chang S, Burton E, Butowski N and MalecM (2006) Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neuro. Oncol. 8, 67–78.
119. Pu P, Kang C, Li J, Jiang H and Cheng J (2006) The effects of antisense AKT2 RNA on the inhibition of malignant glioma cell growth in vitro and in vivo. J. Neurooncol.76, 1–11.
120. Rao G, Pedone CA, Del Valle L, Reiss K, Holland E C and Fults D W (2004) Sonic hedgehog and insulin-like growth factor signalling synergize to induce medulloblastoma formation from nestinexpressing neural progenitors in mice. Oncogene 23, 6156– 6162.
121. Rasheed B K, Stenzel T T, McLendon R E, Parsons R, Friedman A H, Friedman H S, Bigner D D and Bigner S H (1997) PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res. 57, 4187-4190.
122. Raynaud FI, Eccles S, Clarke PA, Hayes A, Nutley B and Alix S (2007) Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res. 67, 5840– 5850.
123. Reis R M, Konu-Lebleblicioglu D, Lopes J M, Kleihues P and Ohgaki H (2000) Genetic pro.le of gliosarcomas. Am. J. Pathol.156, 425-432.
124. Rich J N, Reardon D A, Peery T, Dowell J M, Quinn J A and Penne K L (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol. 22, 133–142.
125. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J and Szabo S (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554.
126. Sano T, Lin H, Chen X, Langford L A, Koul D, Bondy M L, Hess K R, Myers J N, Hong Y K, Yung W K and Steck P A (1999) Differential expression of MMAC/Pten in glioblastoma multiforme: Relationship to localization and prognosis. Cancer Res. 59, 1820-1824.
127. Sasaki H, Zlatescu M C, Betensky R A, Ino Y, Cairncross J G and Louis D N (2001) PTEN is a target of chromosome 10q loss in anaplastic oligodendrogliomas and PTEN alterations are associated with poor prognosis. Am. J. Pathol. 159, 359-367.
128. Scheid M P and Woodgett J R (2001) PKB/AKT: Functional insights from genetic models. Nat. Rev. Mol. Cell Biol. 2, 760-768.
129. Schlegel J, Piontek G and Mennel H D (2002) Activation of the antiapoptoticAkt/protein kinase B pathway in human malignant gliomas in vivo. Anticancer Res. 22, 2837–2840.
130. Schmidt E E, Ichimura K, Goike H M, Moshref A, Liu L and Collins V P (1999) Mutational pro.le of the PTEN gene in primary human astrocytic tumors and cultivated xenografts. J. Neuropathol. Exp. Neurol. 58, 1170-1183.
131. Shannon P, Sabha N, Lau N, Kamnasaran D, Gutmann D H and Guha A (2005) Pathological and molecular progression of astrocytomas in a GFAP: 12 V-Ha-Ras mouse astrocytoma model. Am. J. Pathol. 167, 859–867.
132. Shayesteh L, Lu Y, Kuo W L, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills G B and Gray J W (1999) PIK3CA is implicated as an oncogene in ovarian cancer. Nat. Genet. 21, 99-102.
133. She Q B, Solit D B, Ye Q, O’Reilly K E, Lobo J and Rosen N (2005) The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell 8, 287–297.
134. Simpson L and Parsons R (2001) PTEN: life as a tumor suppressor. Exp. Cell Res. 264, 29–41.
135. Singh S K, Hawkins C, Clarke I D, Squire J A, Bayani J and Hide T (2004) Identification of human brain tumour initiating cells. Nature 432, 396–401.
136. Smith J S, Tachibana I, Passe S M, Huntley B K, Borell T J, Iturria N, O’Fallon J R, Schaefer P L, Scheithauer B W, James C D, Buckner J C and Jenkins R B (2001) PTEN mutation, EGFR ampli.cation, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J. Natl. Cancer Inst. 93, 1246-1256.
137. Sonoda Y, Ozawa T, Aldape K D, Deen D F, Berger M S and Pieper R O (2001) Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. Cancer Res. 61, 6674-6678.
138. Stambolic V, MacPherson D, Sas D, Lin Y, Snow B and Jang Y (2001) Regulation of PTEN transcription by p53. Mol. Cell. 8, 317– 325.
139. Steck P A, Perhouse M A, Jasser S A, Yung W K A, Lin H, Ligon A Z, Langford L A, Baumgard M L, Haitter T, Davis T, Frye C, Hu R, Swedlund B, Teng D H F and Tavtigian S V (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23. 3 that is mutated in multiple advanced cancer. Nat. Genet. 15, 356–362.
140. Sun M, Wang G, Paciga J E, Feldman R I, Yuan Z Q, Ma X L, Shelley S A, Jove R, Tsichlis P N, Nicosia S V and Cheng J Q (2001) AKT1/PKB kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am. J. Pathol. 159, 431-437.
141. Tachibana I, Smith J S, Sato K, Hosek S M, Kimmel D W and Jenkins R B (2000) Investigation of germline PTEN, p53, p16(INK4A)/p14 (ARF), and CDK4 alterations in familial glioma. Am. J. Med. Genet. 92, 136-141.
142. Tamura M, Gu J, Takino T and Yamada K M (1999) Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: Differential involvement of focal adhesion kinase and p130Cas. Cancer Res. 59, 442-449.
143. Tamura M, Gu J, Matsumoto K, Aota S, Parsons R and Yamada K M (1998) Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor Pten. Science 280, 1614-1617.
144. Teng D H, Hu R, Lin H, Davis T, Iliev D, Frye C, Swedlund B, Hansen K L, Vinson V L, Gumpper K L, Ellis L, El-Naggar A, Frazier M, Jasser S, Langford L A, Lee J, Mills G B, Pershouse M A, Pollack R E, Tornos C, Troncoso P, Yung W K, Fujii G, Berson A and Steck P A(1997) MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res, 57, 5221-5225.
145. Tian X X, Pang J C, To S S and Ng H K (1999) Restoration of wild-type Pten expression leads to apoptosis, induces differentiation, and reduces telomerase activity in human glioma cells. J. Neuropathol. Exp. Neurol.58, 472-479.
146. Tohma Y, Gratas C, Biernat W, Peraud A, Fukuda M, Yonekawa Y, Kleihues P and Ohgaki H (1998) PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J. Neuropathol. Exp. Neurol. 57, 684-689.
147. Tortosa A, Ino Y, Odell N, Swilley S, Sasaki H, Louis D N and Henson J W (2000) Molecular genetics of radiographically defined de novo glioblastoma multiforme. Neuropathol. Appl. Neurobiol. 26, 544-552.
148. Tsou H C, Teng D, Ping XL, Broncolini V, Davis T, Hu R, Xie X-X, Gruener A C, Schrager C A, Christiano A M, Eng C, Steck P, Ott J, Tavtigian S V and Peacocke M (1997) Role of MMAC1 mutations in early onset breast cancer: causative in association with Cowden’s syndrome and excluded in BRCA1-negative cases. Am. J. Hum. Genet. 61, 1036–1043.
149. Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M and Sticker M (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200– 205.
150. Walker C, Joyce K A, Thompson-Hehir J, Davies M P, Gibbs F E, Halliwell N, Lloyd B H, Machell Y, Roebuck M M, Salisbury J, Sibson D R, Du Plessis D, Broome J and Rossi M L (2001) Characterisation of molecular alterations in microdissected archival gliomas. Acta Neuropathol. 101, 321-333.
151. Wang MY, Lu KV, Zhu S, Dia EQ, Vivanco I and Shackleford G M (2006) Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells. Cancer Res. 66, 7864–7869.
152. Wang D, Huang H J, Kazlauskas A and Cavenee W K (1999) Induction of vascular endothelial growth factor expression in endothelial cells by platelet-derived growth factor through the activation of phosphatidylinositol 3-kinase. Cancer Res.59, 1464-1472.
153. Wang D, Huang H J, Kazlauskas A and Cavenee W K (1999) Induction of vascular endothelial growth factor expression in endothelial cells by platelet-derived growth factor through the activation of phosphatidylinositol 3-kinase. Cancer Res. 59, 1464-1472.
154. Wang S I, Puc J, Li J, Bruce J N, Cairns P, Sidransky D and Parsons R (1997) Somatic mutations of PTEN in glioblastoma multiforme. CancerRes. 57, 4183-4186.
155. Watanabe K, Peraud A, Gratas C, Wakai S, Kleihues P and Ohgaki H (1998) p53and PTENgene mutations in gemistocytic astrocytomas. Acta Neuropathol. 95, 559-564.
156. Wick W, Furnari F B, Naumann U, Cavenee W K and Weller M (1999) PTEN gene transfer in human malignant glioma: Sensitization to irradiation and CD95L-induced apoptosis. Oncogene 18, 3936-3943.
157. Wei Q, Clarke L, Scheidenhelm DK, Qian B, Tong A and Sabha N (2006) High-grade glioma formation results from postnatal pten loss or mutant epidermal growth factor receptor expression in a transgenicmouse glioma model. Cancer Res. 66, 7429–7437.
158. Wechsler-Reya R and Scott M P (2001) The developmental biology of brain tumors. Ann. Rev. Neurosci. 24, 385-428.
159. Wen S, Stolarov J, Myers M P, Su J D, Wigler M H, Tonks N K and Durden D L (2001) Pten controls tumor-induced angiogenesis. Proc. Natl. Acad. Sci. U.S.A. 98, 4622-4627.
160. Weng L P, Brown J L and Eng C (2001b) Pten coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and upregulating p27 via its lipid phosphatase activity in a breast cancer model. Hum. Mol. Genet.10, 599-604.
161. Wiencke J K, Zheng S, Jelluma N, Tihan T, Vandenberg S and Tamguney T (2007) Methylation of the PTEN promoter defines lowgrade gliomas and secondary glioblastoma. Neuro. Oncol. 9, 271–279.
162. Wu R C, Li X and Schonthal A H (2000) Transcriptionalactivationof p21WAF1 by Pten/MMAC1tumor suppressor. Mol. Cell. Biochem. 203, 59-71.
163. Xiao A, Wu H, Pandolfi P P, Louis D N and Van Dyke T (2002) Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation. Cancer Cell 1, 157–168.
164. Xiao A, Yin C, Yang C, Di Cristofano A, Pandolfi P P and Van Dyke T (2005) Somatic induction of Pten loss in a preclinical astrocytoma model reveals major roles in disease progression and avenues for target discovery and validation. Cancer Res. 65, 5172–5180.
165. Yang ZZ, Tschopp O, Di-Poi N, Bruder E, Baudry A and Dummler B (2005) Dosage-dependent effects of Akt1/protein kinase Balpha (PKBalpha) and Akt3/PKBgamma on thymus, skin, and cardiovascular and nervous system development in mice. Mol Cell Biol. 25, 10407–10418.
166. Yilmaz O H, Valdez R, Theisen B K, Guo W, Ferguson D O and Wu H (2006) Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482.
167. Yue Q, Groszer M, Gil JS, Berk AJ, Messing A and Wu H (2005) PTEN deletion in Bergmann glia leads to premature differentiation and affects laminar organization. Development 132, 3281–3291.
168. Zhang C L, Tada M, Kobayashi H, Nozaki M, Moriuchi T and Abe H (2000) Detection of PTEN nonsense mutation and psiPTEN expression in central nervous system high-grade astrocytic tumors by a yeast-based stop codon assay. Oncogene 19, 4346-4353.
169. Zhou J, Wulfkuhle J, Zhang H, Gu P, Yang Y and Deng J (2007) Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci USA,104, 16158–16163.
170. Zhou XP, Marsh DJ, Morrison CD, Chaudhury AR, Maxwell M and Reifenberger G (2003) Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults. Am. J. Hum. Genet. 73, 1191–1198.
171. Zhou B P, Liao Y, Xia W, Spohn B, Lee M H and Hung M C (2001b) Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat. Cell Biol. 3, 245-252.
172. Zhou X P, Li Y J, Hoang-Xuan K, Laurent-Puig P, Mokhtari K, Longy M, Sanson M, Delattre J Y, Thomas G and Hamelin R (1999a) Mutational analysis of the PTEN gene in gliomas: Molecular and pathological correlations. Int. J. Cancer 84, 150-154.
173. Zhu Y and Parada L F (2002) The molecular and genetic basis of neurological tumours. Nat. Rev. Cancer 2, 616–626.
174. Zori R T, Marsh D J, Graham G E, Marliss E B and Eng C (1998) Germline PTEN mutation in a family with Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. Am. J. Med. Genet. 80, 399–402.
175. Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk A R, Ryan H E, Johnson R S, Jefferson A B, Stokoe D and Giaccia A J (2000) Loss of Pten facilitates HIF-1-mediated gene expression. Genes Dev. 14, 391-396.