Regulator of Phosphoinositide 3-Kinase Signal Transduction
  • Jen Jen Yeh
  • William R. Sellers
Part of the Cancer Drug Discovery and Development book series (CDD&D)


The chromosome (chr) region spanning 10q22–10q25 exhibits loss of heterozygosity (LOH) in multiple tumor types, including carcinoma of the prostate, endometrium, breast, kidney, and thyroid, as well as glioblastoma, melanoma, and meningioma (1–14). In addition, the gene for Cowden disease (CD), an autosomal dominant familial cancer syndrome that is characterized by multiple hamartomas of the skin, breast, thyroid, and intestines, and an increased risk of breast and thyroid malignancies, has been localized to chr bands 10q22–23 (15) by linkage analysis. Microcell-mediated transfer of chr 10q into glioblastoma cells inhibits soft-agar colony formation and tumor formation in nude mice (16). Likewise, chr transfers of 10q into rat prostate cancer (PC) cells suppresses the metastatic ability of the highly metastatic parental cells (17). Taken together, these findings suggest the presence of one or more tumor suppressor genes (TSGs) in the chr 10q22–25 region. In 1997, the TSG phosphate and tensin homolog deleted on chr 10 (PTEN)/mutated in multiple advanced cancers 1 (MMAC1)/transforming growth factor Fβ-regulated and epithelial cell-enriched phosphatase (TEP1), located on chr subband 10q23.3, was identified by three independent groups (18–20). Mutational analysis of the nine coding exons of PTEN/MMAC1/TEP1 (hereafter referred to as PTEN) demonstrated germ-line mutations in the related familial hamartoma syndromes, CD and Bannayan-Zonana syndrome (BZS), and LOH accompanied by somatic mutation of the remaining allele in multiple tumor types.


Endometrial Carcinoma LNCaP Cell PTEN Gene PTEN Mutation Primary Prostate Cancer 
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  1. 1.
    Isshiki K, Elder DE, Guerry D, Linnenbach AJ. Chromosome 10 allelic loss in malignant melanoma. Genes Chromosomes Cancer 1993; 8:178–184.PubMedCrossRefGoogle Scholar
  2. 2.
    Thrash-Bingham CA, Greenberg RE, Howard S, Bruzel A, Bremer M, Goll A, et al. Comprehensive allelotyping of human renal cell carcinomas using microsatellite DNA probes. Proc Natl Acad Sci USA 1995; 92:2854–2858.PubMedCrossRefGoogle Scholar
  3. 3.
    Simon M, von Deimling A, Larson JJ, Wellenreuther R, Kaskel P, Waha A, et al. Allelic losses on chromosomes 14, 10, and 1 in atypical and malignant meningiomas: a genetic model of meningioma progression. Cancer Res 1995; 55:4696–4701.PubMedGoogle Scholar
  4. 4.
    Zedenius J, Wallin G, Svensson A, Bovee J, Hoog A, Backdahl M, Larsson C. Deletions of the long arm of chromosome 10 in progression of follicular thyroid tumors. Hum Genet 1996; 97:299–303.PubMedCrossRefGoogle Scholar
  5. 5.
    Petersen I, Langreck H, Wolf G, Schwendel A, Psille R, Vogt P, et al. Small-cell lung cancer is characterized by a high incidence of deletions on chromosomes 3p, 4q, 5q, lOq, 13q and 17p. Br J Cancer 1997; 75:79–86.PubMedCrossRefGoogle Scholar
  6. 6.
    Virmani AK, Fong KM, Kodagoda D, McIntire D, Hung J, Tonk V, Minna JD, Gazdar AF. Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types. Genes Chromosomes Cancer 1998; 21:308–319.PubMedCrossRefGoogle Scholar
  7. 7.
    Lamszus K, Kluwe L, Matschke J, Meissner H, Laas R, Westphal M. Allelic losses at 1p, 9q, lOq, 14q, and 22q in the progression of aggressive meningiomas and undifferentiated meningeal sarcomas. Cancer Genet Cytogenet 1999; 110:103–110.PubMedCrossRefGoogle Scholar
  8. 8.
    Rebbeck TR, Godwin AK, Buetow KH. Variability in loss of constitutional heterozygosity across loci and among individuals: association with candidate genes in ductal breast carcinoma. Mol Carcinog 1996; 17:117–125.PubMedCrossRefGoogle Scholar
  9. 9.
    Sourvinos G, Kiaris H, Tsikkinis A, Vassilaros S, Spandidos DA. Microsatellite instability and loss of heterozygosity in primary breast tumours. Tumour Biol 1997; 18:157–166.PubMedCrossRefGoogle Scholar
  10. 10.
    Rasheed BK, McLendon RE, Friedman HS, Friedman AH, Fuchs HE, Bigner DD, Bigner SH. Chromosome 10 deletion mapping in human gliomas: a common deletion region in 10q25. Oncogene 1995; 10:2243–2246.PubMedGoogle Scholar
  11. 11.
    Gray IC, Phillips SM, Lee SJ, Neoptolemos JP, Weissenbach J, Spurr NK. Loss of the chromosomal region 10q23–25 in prostate cancer. Cancer Res 1995; 55:4800–4803.PubMedGoogle Scholar
  12. 12.
    Jones MH, Koi S, Fujimoto I, Hasumi K, Kato K, Nakamura Y. Allelotype of uterine cancer by analysis of RFLP and microsatellite polymorphisms: frequent loss of heterozygosity on chromosome arms 3p, 9q, lOq, and 17p. Genes Chromosomes Cancer 1994; 9:119–123.PubMedCrossRefGoogle Scholar
  13. 13.
    Marsh DJ, Zheng Z, Zedenius J, Kremer H, Padberg GW, Larsson C, Longy M, Eng C. Differential loss of heterozygosity in the region of the Cowden locus within 10q22–23 in follicular thyroid adenomas and carcinomas. Cancer Res 1997; 57:500–503.PubMedGoogle Scholar
  14. 14.
    Bose S, Wang SI, Terry MB, Hibshoosh H, Parsons R. Allelic loss of chromosome 10q23 is associated with tumor progression in breast carcinomas. Oncogene 1998; 17:123–127.PubMedCrossRefGoogle Scholar
  15. 15.
    Nelen MR, van Staveren WC, Peeters EA, Hassel MB, Gorlin RJ, Hamm H, et al. Germline mutations in the PTEN/MMAC 1 gene in patients with Cowden disease. Hum Mol Genet 1997; 6:1383–1387.PubMedCrossRefGoogle Scholar
  16. 16.
    Pershouse MA, Stubblefield E, Hadi A, Killary AM, Yung WK, Steck PA. Analysis of the functional role of chromosome 10 loss in human glioblastomas. Cancer Res 1993; 53:5043–5050.PubMedGoogle Scholar
  17. 17.
    Nihei N, Ichikawa T, Kawana Y, Kuramochi H, Kugo H, Oshimura M, et al. Localization of metastasis suppressor gene(s) for rat prostatic cancer to the long arm of human chromosome 10. Genes Chromosomes Cancer 1995; 14:112–119.PubMedCrossRefGoogle Scholar
  18. 18.
    Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997; 15:356–362.PubMedCrossRefGoogle Scholar
  19. 19.
    Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 1997; 57:2124–2129.PubMedGoogle Scholar
  20. 20.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997; 275:1943–1947.PubMedCrossRefGoogle Scholar
  21. 21.
    Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet 1998; 7:507–515.PubMedCrossRefGoogle Scholar
  22. 22.
    Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 1997; 16:64–67.PubMedCrossRefGoogle Scholar
  23. 23.
    Boni R, Vortmeyer AO, Burg G, Hofbauer G, Zhuang Z. The PTEN tumour suppressor gene and malignant melanoma. Melanoma Res 1998; 8:300–302.PubMedCrossRefGoogle Scholar
  24. 24.
    Bostrom J, Cobbers JM, Wolter M, Tabatabai G, Weber RG, Lichter P, Collins VP, Reifenberger G. Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm IOq. Cancer Res 1998; 58:29–33.PubMedGoogle Scholar
  25. 25.
    Ueda K, Nishijima M, Inui H, Watatani M, Yayoi E, Okamura J, et al. Infrequent mutations in the PTEN/MMAC1 gene among primary breast cancers. Jpn J Cancer Res 1998; 89:17–21.PubMedCrossRefGoogle Scholar
  26. 26.
    Peters N, Wellenreuther R, Rollbrocker B, Hayashi Y, Meyer-Puttlitz B, Duerr EM, et al. Analysis of the PTEN gene in human meningiomas. Neuropathol Appl Neurobiol 1998; 24:3–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Pesche S, Latil A, Muzeau F, Cussenot O, Fournier G, Longy M, Eng C, Lidereau R. PTEN/MMAC1/TEP1 involvement in primary prostate cancers. Oncogene 1998; 16:2879–2883.PubMedCrossRefGoogle Scholar
  28. 28.
    Yokomizo A, Tindall DJ, Drabkin H, Gemmill R, Franklin W, Yang P, et al. PTEN/MMAC1 mutations identified in small cell, but not in non-small cell lung cancers. Oncogene 1998; 17:475–479.PubMedCrossRefGoogle Scholar
  29. 29.
    Tsao H, Zhang X, Benoit E, Haluska FG. Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines. Oncogene 1998; 16:3397–3402.PubMedCrossRefGoogle Scholar
  30. 30.
    Sakai A, Thieblemont C, Wellmann A, Jaffe ES, Raffeld M. PTEN gene alterations in lymphoid neoplasms. Blood 1998; 92:3410–3415.PubMedGoogle Scholar
  31. 31.
    Forgacs E, Biesterveld EJ, Sekido Y, Fong K, Muneer S, Wistuba, II, et al. Mutation analysis of the PTEN/MMAC1 gene in lung cancer. Oncogene 1998; 17:1557–1565.PubMedCrossRefGoogle Scholar
  32. 32.
    Davies MP, Gibbs FE, Halliwell N, Joyce KA, Roebuck MM, Rossi ML, et al. Mutation in the PTEN/MMAC1 gene in archival low grade and high grade gliomas. Br J Cancer 1999; 79:1542–1548.PubMedCrossRefGoogle Scholar
  33. 33.
    Aveyard JS, Skilleter A, Habuchi T, Knowles MA. Somatic mutation of PTEN in bladder carcinoma. Br J Cancer 1999; 80:904–908.PubMedCrossRefGoogle Scholar
  34. 34.
    Chen ST, Yu SY, Tsai M, Yeh KT, Wang JC, Kao MC, Shih MC, Chang JG. Mutation analysis of the putative tumor suppression gene PTEN/MMAC1 in sporadic breast cancer. Breast Cancer Res Treat 1999; 55:85–89.PubMedCrossRefGoogle Scholar
  35. 35.
    Dahia PL, Marsh DJ, Zheng Z, Zedenius J, Komminoth P, Frisk T, et al. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res 1997; 57:4710–4713.PubMedGoogle Scholar
  36. 36.
    Kurose K, Bando K, Fukino K, Sugisaki Y, Araki T, Emi M. Somatic mutations of the PTEN/MMAC1 gene in fifteen Japanese endometrial cancers: evidence for inactivation of both alleles. Jpn J Cancer Res 1998; 89:842–848.PubMedCrossRefGoogle Scholar
  37. 37.
    Freihoff D, Kempe A, Beste B, Wappenschmidt B, Kreyer E, Hayashi Y, et al. Exclusion of a major role for the PTEN tumour-suppressor gene in breast carcinomas. Br J Cancer 1999; 79:754–758.PubMedCrossRefGoogle Scholar
  38. 38.
    Feilotter HE, Nagai MA, Boag AH, Eng C, Mulligan LM. Analysis of PTEN and the 10q23 region in primary prostate carcinomas. Oncogene 1998; 16:1743–1748.PubMedCrossRefGoogle Scholar
  39. 39.
    Duerr EM, Rollbrocker B, Hayashi Y, Peters N, Meyer-Puttlitz B, Louis DN, et al. PTEN mutations in gliomas and glioneuronal tumors. Oncogene 1998; 16:2259–2264.PubMedCrossRefGoogle Scholar
  40. 40.
    Butler MP, Wang SI, Chaganti RS, Parsons R, Dalla-Favera R. Analysis of PTEN mutations and deletions in B-cell non-Hodgkin’s lymphomas. Genes Chromosomes Cancer 1999; 24:322–327.PubMedCrossRefGoogle Scholar
  41. 41.
    Cairns P, Evron E, Okami K, Halachmi N, Esteller M, Herman JG, et al. Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers. Oncogene 1998; 16:3215–3218.PubMedCrossRefGoogle Scholar
  42. 42.
    Simpkins SB, Peiffer-Schneider S, Mutch DG, Gersell D, Goodfellow PJ. PTEN mutations in endometrial cancers with IOq LOH: additional evidence for the involvement of multiple tumor suppressors. Gynecol Oncol 1998; 71:391–395.PubMedCrossRefGoogle Scholar
  43. 43.
    Rhei E, Kang L, Bogomolniy F, Federici MG, Borgen PI, Boyd J. Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Cancer Res 1997; 57:3657–3659.PubMedGoogle Scholar
  44. 44.
    Guldberg P, thor Straten P, Birck A, Ahrenkiel V, Kirkin AF, Zeuthen J. Disruption of the MMAC 1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res 1997; 57:3660–3663.PubMedGoogle Scholar
  45. 45.
    Wang SI, Puc J, Li J, Bruce JN, Cairns P, Sidransky D, Parsons R. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res 1997; 57:4183–4186.PubMedGoogle Scholar
  46. 46.
    Rasheed BK, Stenzel TT, McLendon RE, Parsons R, Friedman AH, Friedman HS, Bigner DD, Bigner SH. PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res 1997; 57:4187–4190.PubMedGoogle Scholar
  47. 47.
    Tashiro H, Blazes MS, Wu R, Cho KR, Bose S, Wang SI, et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res 1997; 57:3935–3940.PubMedGoogle Scholar
  48. 48.
    Risinger JI, Hayes AK, Berchuck A, Barrett JC. PTEN/MMAC1 mutations in endometrial cancers. Cancer Res 1997; 57:4736–4738.PubMedGoogle Scholar
  49. 49.
    Halachmi N, Halachmi S, Evron E, Cairns P, Okami K, Saji M, et al. Somatic mutations of the PTEN tumor suppressor gene in sporadic follicular thyroid tumors. Genes Chromosomes Cancer 1998; 23:239–243.PubMedCrossRefGoogle Scholar
  50. 50.
    Steck PA, Lin H, Langford LA, Jasser SA, Koul D, Yung WK, Pershouse MA. Functional and molecular analyses of 10q deletions in human gliomas. Genes Chromosomes Cancer 1999; 24:135–143.PubMedCrossRefGoogle Scholar
  51. 51.
    Somerville RP, Shoshan Y, Eng C, Barnett G, Miller D, Cowell JK. Molecular analysis of two putative tumour suppressor genes, PTEN and DMBT, which have been implicated in glioblastoma multiforme disease progression.Oncogene 1998; 17:1755–1757.Google Scholar
  52. 52.
    Rasheed BK, Wiltshire RN, Bigner SH, Bigner DD. Molecular pathogenesis of malignant gliomas. Curr Opin Oncol 1999; 11:162–167.PubMedCrossRefGoogle Scholar
  53. 53.
    Liu W, James CD, Frederick L, Alderete BE, Jenkins RB. PTEN/MMAC1 mutations and EGFR amplification in glioblastomas. Cancer Res 1997; 57:5254–5257.PubMedGoogle Scholar
  54. 54.
    Gray IC, Stewart LM, Phillips SM, Hamilton JA, Gray NE, Watson GJ, Spurr NK, Snary D. Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN. Br J Cancer 1998; 78:1296–1300.PubMedCrossRefGoogle Scholar
  55. 55.
    Cairns P, Okami K, Halachmi S, Halachmi N, Esteller M, Herman JG, et al. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res 1997; 57:4997–5000.PubMedGoogle Scholar
  56. 56.
    McMenamin ME, Soung P, Perera S, Kaplan I, Loda M, Sellers WR. Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res 1999; 59:4291–4296.PubMedGoogle Scholar
  57. 57.
    Komiya A, Suzuki H, Ueda T, Yatani R, Emi M, Ito H, Shimazaki J. Allelic losses at loci on chromosome 10 are associated with metastasis and progression of human prostate cancer. Genes Chromosomes Cancer 1996; 17:245–253.PubMedCrossRefGoogle Scholar
  58. 58.
    Healy E, Belgaid C, Takata M, Harrison D, Zhu NW, Burd DA, et al. Prognostic significance of allelic losses in primary melanoma. Oncogene 1998; 16:2213–2218.PubMedCrossRefGoogle Scholar
  59. 59.
    Maxwell GL, Risinger JI, Gumbs C, Shaw H, Bentley RC, Barrett JC, Berchuck A, Futreal PA. Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias. Cancer Res 1998; 58:2500–2503.PubMedGoogle Scholar
  60. 60.
    Sellers WR, Kaelin WG, Jr. Role of the retinoblastoma protein in the pathogenesis of human cancer. J Clin Oncol 1997; 15:3301–3312.PubMedGoogle Scholar
  61. 61.
    Feilotter HE, Coulon V, McVeigh JL, Boag AH, Dorion-Bonnet F, Duboue B, et al. Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma. Br J Cancer 1999; 79:718–723.PubMedCrossRefGoogle Scholar
  62. 62.
    FitzGerald MG, Marsh DJ, Wahrer D, Bell D, Caron S, Shannon KE, et al. Germline mutations in PTEN are an infrequent cause of genetic predisposition to breast cancer. Oncogene 1998; 17:727–731.CrossRefGoogle Scholar
  63. 63.
    Whang YE, Wu X, Suzuki H, Reiter RE, Tran C, Vessella RL, et al. Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci USA 1998; 95:5246–5250.PubMedCrossRefGoogle Scholar
  64. 64.
    Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP. Pten is essential for embryonic development and tumour suppression. Nat Genet 1998; 19:348–355.PubMedCrossRefGoogle Scholar
  65. 65.
    Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J, et al. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci USA 1999; 96:6199–6204.PubMedCrossRefGoogle Scholar
  66. 66.
    Di Cristofano A, Kotsi P, Peng YF, Cordon-Cardo C, Elkon KB, Pandolfi PP. Impaired fas response and autoimmunity in Pten(+/-) mice. Science 1999; 285:2122–2125.PubMedCrossRefGoogle Scholar
  67. 67.
    Mollenhauer J, Wiemann S, Scheurlen W, Korn B, Hayashi Y, Wilgenbus KK, von Deimling A, Poustka A. DMBT1, a new member of the SRCR superfamily, on chromosome 10q25.3–26.1 is deleted in malignant brain tumours. Nat Genet 1997; 17:32–39.PubMedCrossRefGoogle Scholar
  68. 68.
    Wechsler DS, Hawkins AL, Li X, Jabs EW, Griffin CA, Dang CV. Localization of the human Mxil transcription factor gene (MXI1) to chromosome 10q24-q25. Genomics 1994; 21:669–672.PubMedCrossRefGoogle Scholar
  69. 69.
    Prochownik EV, Eagle Grove L, Deubler D, Zhu XL, Stephenson RA, Rohr LR, Yin X, Brothman AR. Commonly occurring loss and mutation of the MXI1 gene in prostate cancer. Genes Chromosomes Cancer 1998; 22:295–304.PubMedCrossRefGoogle Scholar
  70. 70.
    Kuczyk MA, Serth J, Bokemeyer C, Schwede J, Herrmann R, Machtens S, et al. The MXII tumor suppressor gene is not mutated in primary prostate cancer. Oncol Rep 1998; 5:213–216.PubMedGoogle Scholar
  71. 71.
    Edwards SM, Dearnaley DP, Ardern-Jones A, Hamoudi RA, Easton DF, Ford D, et al. No germline mutations in the dimerization domain of MXI1 in prostate cancer clusters. The CRC/BPG UK Familial Prostate Cancer Study Collaborators. Cancer Research Campaign/British Prostate Group. Br J Cancer 1997; 76:992–1000.PubMedCrossRefGoogle Scholar
  72. 72.
    Eagle LR, Yin X, Brothman AR, Williams BJ, Atkin NB, Prochownik EV. Mutation of the MXII gene in prostate cancer. Nat Genet 1995; 9:249–255.PubMedCrossRefGoogle Scholar
  73. 73.
    Kawamata N, Park D, Wilczynski S, Yokota J, Koeffler HP. Point mutations of the Mxil gene are rare in prostate cancers. Prostate 1996; 29:191–193.PubMedCrossRefGoogle Scholar
  74. 74.
    Kim SK, Ro JY, Kemp BL, Lee JS, Kwon TJ, Hong WK, Mao L. Identification of two distinct tumorsuppressor loci on the long arm of chromosome 10 in small cell lung cancer. Oncogene 1998; 17:1749–1753.PubMedCrossRefGoogle Scholar
  75. 75.
    Fults D, Pedone CA, Thompson GE, Uchiyama CM, Gumpper KL, Iliev D, et al. Microsatellite deletion mapping on chromosome lOq and mutation analysis of MMAC1, FAS, and MXI1 in human glioblastoma multiforme. Int J Oncol 1998; 12:905–910.PubMedGoogle Scholar
  76. 76.
    Wu W, Kemp BL, Proctor ML, Gazdar AF, Minna JD, Hong WK, Mao L. Expression of DMBT1, a candidate tumor suppressor gene, is frequently lost in lung cancer. Cancer Res 1999; 59:1846–1851.PubMedGoogle Scholar
  77. 77.
    Lin H, Bondy ML, Langford LA, Hess KR, Delclos GL, Wu X, et al. Allelic deletion analyses of MMAC/PTEN and DMBT1 loci in gliomas: relationship to prognostic significance. Clin Cancer Res 1998; 4:2447–2454.PubMedGoogle Scholar
  78. 78.
    Mori M, Shiraishi T, Tanaka S, Yamagata M, Mafune K, Tanaka Y, et al. Lack of DMBT1 expression in oesophageal, gastric and colon cancers. Br J Cancer 1999; 79:211–213.PubMedCrossRefGoogle Scholar
  79. 79.
    Lee SH, Shin MS, Park WS, Kim SY, Dong SM, Pi JH, et al. Alterations of Fas (APO-1/CD95) gene in transitional cell carcinomas of urinary bladder. Cancer Res 1999; 59:3068–3072.PubMedGoogle Scholar
  80. 80.
    Lee SH, Shin MS, Park WS, Kim SY, Kim HS, Han JY, et al. Alterations of Fas (Apo-1/CD95) gene in non-small cell lung cancer. Oncogene 1999; 18:3754–3760.PubMedCrossRefGoogle Scholar
  81. 81.
    Shin MS, Park WS, Kim SY, Kim HS, Kang SJ, Song KY, et al. Alterations of Fas (Apo-1/CD95) gene in cutaneous malignant melanoma. Am J Pathol 1999; 154:1785–1791.PubMedCrossRefGoogle Scholar
  82. 82.
    Abdel-Rahman W, Arends M, Morris R, Ramadan M, Wyllie A. Death pathway genes Fas (Apo1/CD95) and Bik (Nbk) show no mutations in colorectal carcinomas [letter]. Cell Death Differ 1999; 6:387–388.PubMedCrossRefGoogle Scholar
  83. 83.
    Butler LM, Hewett PJ, Butler WJ, Cowled PA. Down-regulation of Fas gene expression in colon cancer is not a result of allelic loss or gene rearrangement. Br J Cancer 1998; 77:1454–1459.PubMedCrossRefGoogle Scholar
  84. 84.
    Chi H, Tiller GE, Dasouki MJ, Romano PR, Wang J, O’Keefe RJ, et al. Multiple inositol polyphosphate phosphatase: evolution as a distinct group within the histidine phosphatase family and chromosomal localization of the human and mouse genes to chromosomes 10q23 and 19. Genomics 1999; 56:324–336.PubMedCrossRefGoogle Scholar
  85. 85.
    Cheney IW, Johnson DE, Vaillancourt MT, Avanzini J, Morimoto A, Demers GW, et al. Suppression of tumorigenicity of glioblastoma cells by adenovirus-mediated MMAC1/PTEN gene transfer. Cancer Res 1998; 58:2331–2334.PubMedGoogle Scholar
  86. 86.
    Li DM, Sun H. PTEN/MMAC 1/TEP 1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci USA 1998; 95:15,406–15,411.Google Scholar
  87. 87.
    Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, et al. The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. Proc Natl Acad Sci USA 1998; 95:13,513–13,518.CrossRefGoogle Scholar
  88. 88.
    Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL. The PTEN/MMAC 1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci USA 1998; 95:15,587–15,591.Google Scholar
  89. 89.
    Robertson GP, Furnari FB, Miele ME, Glendening MJ, Welch DR, Fountain JW, et al. In vitro loss of heterozygosity targets the PTEN/MMAC 1 gene in melanoma. Proc Natl Acad Sci USA 1998; 95:9418–9423.PubMedCrossRefGoogle Scholar
  90. 90.
    Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, et al. Mutation of Pten/Mmac 1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci USA 1999; 96:1563–1568.PubMedCrossRefGoogle Scholar
  91. 91.
    Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol 1998; 8:1169–1178.PubMedCrossRefGoogle Scholar
  92. 92.
    Haynie DT, Ponting CP. The N-terminal domains of tensin and auxilin are phosphatase homologues. Protein Science 1996; 5:2643–2646.PubMedCrossRefGoogle Scholar
  93. 93.
    Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, Parsons R, Tonks NK. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Nall Acad Sci USA 1997; 94:9052–9057.CrossRefGoogle Scholar
  94. 94.
    Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC 1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998; 273:13,375–13,378.CrossRefGoogle Scholar
  95. 95.
    Fruman DA, Rameh LE, Cantley LC. Phosphoinositide binding domains: embracing 3-phosphate. Cell 1999; 97:817–820.PubMedCrossRefGoogle Scholar
  96. 96.
    Anderson RA, Boronenkov IV, Doughman SD, Kunz J, Loijens JC. Phosphatidylinositol phosphate kinases, a multifaceted family of signaling enzymes. J Biol Chem 1999; 274:9907–9910.PubMedCrossRefGoogle Scholar
  97. 97.
    Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 1999; 96:4240–4245.PubMedCrossRefGoogle Scholar
  98. 98.
    Khwaja A, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J 1997; 16:2783–2793.PubMedCrossRefGoogle Scholar
  99. 99.
    Toker A, Cantley LC. Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 1997; 387:673–676.PubMedCrossRefGoogle Scholar
  100. 100.
    Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 1998; 10:262–267.PubMedCrossRefGoogle Scholar
  101. 101.
    Kohn AD, Takeuchi F, Roth RA. Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. J Biol Chem 1996; 271:21,920–21,926.Google Scholar
  102. 102.
    Alessi DR, Cohen P. Mechanism of activation and function of protein kinase B. Curr Opin Genet Dey 1998; 8:55–62.CrossRefGoogle Scholar
  103. 103.
    Balendran A, Casamayor A, Deak M, Paterson A, Gaffney P, Currie R, Downes CP, Alessi DR. PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2. Curr Biol 1999; 9:393–404.PubMedCrossRefGoogle Scholar
  104. 104.
    Bellacosa A, Testa JR, Staal SP, Tsichlis PN. A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 1991; 254:274–277.PubMedCrossRefGoogle Scholar
  105. 105.
    Coffer PJ, Woodgett JR. Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families [published erratum appears in Eur J Biochem 1992; 205:1217]. Eur J Biochem 1991; 201:475–481.Google Scholar
  106. 106.
    Jones PF, Jakubowicz T, Pitossi FJ, Maurer F, Hemmings BA. Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily. Proc Natl Acad Sci USA 1991; 88:4171–4175.PubMedCrossRefGoogle Scholar
  107. 107.
    Aoki M, Batista O, Bellacosa A, Tsichlis P, Vogt PK. The akt kinase: molecular determinants of oncogenicity. Proc Natl Acad Sci USA 1998; 95:14,950–14,955.CrossRefGoogle Scholar
  108. 108.
    Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 1999; 398:630–634.PubMedCrossRefGoogle Scholar
  109. 109.
    Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999; 96:857–868.PubMedCrossRefGoogle Scholar
  110. 110.
    Tang ED, Nunez G, Barr FG, Guan KL. Negative regulation of the forkhead transcription factor FKHR by Akt. J Biol Chem 1999; 274:16,741–16,746.Google Scholar
  111. 111.
    Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995; 378:785–789.PubMedCrossRefGoogle Scholar
  112. 112.
    Burgering BM, Coffer PJ. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 1995; 376:599–602.PubMedCrossRefGoogle Scholar
  113. 113.
    Gingras AC, Kennedy SG, O’Leary MA, Sonenberg N, Hay N. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dey 1998; 12:502–513.CrossRefGoogle Scholar
  114. 114.
    Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-KappaB activation by tumor necrosis factor requires the Akt serine-threonine kinase. Nature 1999; 401:82–85.PubMedCrossRefGoogle Scholar
  115. 115.
    Romashkova JA, Makarov SS. NF-KappaB is a target of anti-apoptotic PDGF signalling. Nature 1999; 401:86–90.PubMedCrossRefGoogle Scholar
  116. 116.
    Kane LP, Shapiro VS, Stokoe D, Weiss A. Induction of NF-kappaB by the Akt/PKB kinase. Curr Biol 1999; 9:601–604.PubMedCrossRefGoogle Scholar
  117. 117.
    Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999; 399:601–605.PubMedCrossRefGoogle Scholar
  118. 118.
    Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999; 399:597–601.PubMedCrossRefGoogle Scholar
  119. 119.
    Michell BJ, Griffiths JE, Mitchelhill KI, Rodriguez-Crespo I, Tiganis T, Bozinovski S, et al. The Akt kinase signals directly to endothelial nitric oxide synthase. Curr Biol 1999; 12:845–848.CrossRefGoogle Scholar
  120. 120.
    Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998; 282:1318–1321.PubMedCrossRefGoogle Scholar
  121. 121.
    Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91:231–241.PubMedCrossRefGoogle Scholar
  122. 122.
    Gingras AC, Gygi SP, Raught B, Polakiewicz RD, Abraham RT, Hoekstra MF, Aebersold R, Sonenberg N. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dey 1999; 13:1422–1437.CrossRefGoogle Scholar
  123. 123.
    Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 1998; 95:29–39.PubMedCrossRefGoogle Scholar
  124. 124.
    Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera S, Roberts TM, Sellers WR. Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci USA 1999; 96:2110–2115.PubMedCrossRefGoogle Scholar
  125. 125.
    Haas-Kogan D, Shalev N, Wong M, Mills G, Yount G, Stokoe D. Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr Biol 1998; 8:1195–1198.PubMedCrossRefGoogle Scholar
  126. 126.
    Dahia PLM, Aguiar RCT, Alberta J, Kum JB, Caron S, Sill H, et al. PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies. Hum Mol Genet 1999; 8:185–193.PubMedCrossRefGoogle Scholar
  127. 127.
    Li J, Simpson L, Takahashi M, Miliaresis C, Myers MP, Tonks N, Parsons R. The PTEN/MMAC 1 tumor suppressor induces cell death that is rescued by the AKT/protein kinase B oncogene. Cancer Res 1998; 58:5667–5672.PubMedGoogle Scholar
  128. 128.
    Furnari FB, Huang HJ, Cavenee WK. The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer Res 1998; 58:5002–5008.PubMedGoogle Scholar
  129. 129.
    Davies MA, Koul D, Dhesi H, Berman R, McDonnell TJ, McConkey D, Yung WK, Steck PA. Regulation of Akt/PKB activity, cellular growth, and apoptosis in prostate carcinoma cells by MMAC/PTEN. Cancer Res 1999; 59:2551–2556.PubMedGoogle Scholar
  130. 130.
    Hunter T, Pines J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell 1994; 79:573–582.PubMedCrossRefGoogle Scholar
  131. 131.
    Carson JP, Kulik G, Weber MJ. Antiapoptotic signaling in LNCaP prostate cancer cells: a survival signaling pathway independent of phosphatidylinositol 3’-kinase and Akt/protein kinase B. Cancer Res 1999; 59:1449–1453.PubMedGoogle Scholar
  132. 132.
    Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 1997; 277:942–946.PubMedCrossRefGoogle Scholar
  133. 133.
    Morris JZ, Tissenbaum HA, Ruvkun G. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 1996; 382:536–539.PubMedCrossRefGoogle Scholar
  134. 134.
    Paradis S, Ruvkun G. Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 P13 kinase to the DAF-16 transcription factor. Genes Dey 1998; 12:2488–2498.CrossRefGoogle Scholar
  135. 135.
    Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 1997; 389:994–999.PubMedCrossRefGoogle Scholar
  136. 136.
    Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature 1993; 366:461–464.PubMedCrossRefGoogle Scholar
  137. 137.
    Gottlieb S, Ruvkun G. daf-2, daf-16 and daf-23: genetically interacting genes controlling Dauer formation in Caenorhabditis elegans. Genetics 1994; 137:107–120.PubMedGoogle Scholar
  138. 138.
    Larsen PL, Albert PS, Riddle DL. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics 1995; 139:1567–1583.PubMedGoogle Scholar
  139. 139.
    Dorman JB, Albinder B, Shroyer T, Kenyon C. The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans. Genetics 1995; 141:1399–1406.PubMedGoogle Scholar
  140. 140.
    Gil EB, Malone Link E, Liu LX, Johnson CD, Lees JA. Regulation of the insulin-like developmental pathway of Caenorhabditis elegans by a homolog of the PTEN tumor suppressor gene. Proc Natl Acad Sci USA 1999; 96:2925–2930.PubMedCrossRefGoogle Scholar
  141. 141.
    Mihaylova VT, Borland CZ, Manjarrez L, Stern MJ, Sun H. The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway. Proc Nall Acad Sci USA 1999; 96:7427–7432.CrossRefGoogle Scholar
  142. 142.
    Ogg S, Ruvkun G. The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Mol Cell 1998; 2:887–893.PubMedCrossRefGoogle Scholar
  143. 143.
    Rouault JP, Kuwabara PE, Sinilnikova OM, Duret L, Thierry-Mieg D, Billaud M. Regulation of dauer larva development in Caenorhabditis elegans by daf-18, a homologue of the tumour suppressor PTEN. Curr Biol 1999; 9:329–332.PubMedCrossRefGoogle Scholar
  144. 144.
    Maehama T, Dixon JE. PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol 1999; 9:125–128.PubMedCrossRefGoogle Scholar
  145. 145.
    Davies MA, Lu Y, Sano T, Fang X, Tang P, LaPushin R, et al. Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis [published erratum appears in Cancer Res 1999; 59:1167]. Cancer Res 1998; 58:5285–5290.Google Scholar
  146. 146.
    Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 1998; 280:1614–1617.PubMedCrossRefGoogle Scholar
  147. 147.
    Gu J, Tamura M, Yamada KM. Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. J Cell Biol 1998; 143:1375–1383.PubMedCrossRefGoogle Scholar
  148. 148.
    Gu J, Tamura M, Pankov R, Danen EH, Takino T, Matsumoto K, Yamada KM. Shc and FAK differentially regulate cell motility and directionality modulated by PTEN. JCell Biol 1999; 146:389–403.CrossRefGoogle Scholar
  149. 149.
    Tamura M, Gu J, Takino T, Yamada KM. Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas. Cancer Res 1999; 59:442–449.PubMedGoogle Scholar
  150. 150.
    Cao TT, Deacon HW, Reczek D, Bretscher A, von Zastrow M. A Kinase-regulated PDZ-domain interaction controls endocytic sorting of the beta2-adrenergic receptor. Nature 1999; 401:286–290.PubMedCrossRefGoogle Scholar
  151. 151.
    Georgescu MM, Kirsch KH, Akagi T, Shishido T, Hanafusa H. The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region. Proc Natl Acad Sci USA 1999; 96:10,182–10,187.CrossRefGoogle Scholar
  152. 152.
    Suzuki H, Freije D, Nusskern DR, Okami K, Cairns P, Sidransky D, Isaacs WB, Bova GS. Interfocal heterogeneity of PTEN/MMAC 1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res 1998; 58:204–209.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Jen Jen Yeh
  • William R. Sellers

There are no affiliations available

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