Cell cycle regulation after exposure to ionizing radiation;Regulation du cycle cellulaire des cellules exposees aux radiations ionisantes

Bulletin du Cancer

Volumn 86, Issue 4, 1999, Pages 345-357

  Teyssier, Franck ^a   Bay, Jacques Olivier ^b   Dionet, Claude ^b   Verrelle, Pierre ^b  

^a UNIVERSITÉ JEAN MONNET   (France)

^b CENTRE JEAN PERRIN   (France)

Author keywords

Cell cycle checkpoints; Ionizing radiation; Radiosensitization; Signal transduction

Indexed keywords

7 HYDROXYSTAUROSPORINE; CAFFEINE; CYCLIN DEPENDENT KINASE INHIBITOR; DNA DEPENDENT PROTEIN KINASE; METHYLXANTHINE DERIVATIVE; PROTEIN KINASE; PROTEIN KINASE INHIBITOR; PROTEIN P15; PROTEIN P21; PROTEIN P27; PROTEIN P53; STAUROSPORINE; CDKN1A PROTEIN, HUMAN; CYCLIN DEPENDENT KINASE; CYCLIN DEPENDENT KINASE INHIBITOR 1A; CYCLINE; DNA;

APOPTOSIS; CELL CYCLE; CELL CYCLE G1 PHASE; CELL CYCLE G2 PHASE; DNA DAMAGE; DNA REPAIR; ENZYME PHOSPHORYLATION; GENE ACTIVATION; HUMAN; IONIZING RADIATION; MITOSIS INHIBITION; RADIOSENSITIZATION; REVIEW; GENETICS; NEOPLASM; PHYSIOLOGY; RADIATION EXPOSURE; SIGNAL TRANSDUCTION; TUMOR SUPPRESSOR GENE;

APOPTOSIS; CELL CYCLE; CYCLIN-DEPENDENT KINASE INHIBITOR P21; CYCLIN-DEPENDENT KINASES; CYCLINS; DNA; DNA DAMAGE; DNA REPAIR; G1 PHASE; G2 PHASE; GENES, P53; HUMANS; NEOPLASMS; PROTEIN KINASES; SIGNAL TRANSDUCTION; TUMOR SUPPRESSOR PROTEIN P53;

EID: 0033110171     PISSN: 00074551     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (106)

1. Paulovich AG, Toczyski DP, Hartwell LH. When checkpoints fail. Cell 1997; 88: 315-21.
2. Meyn MS. Ataxia-telangiectasia and cellular responses to DNA damage. Cancer Res 1995; 55: 5991-6001.
3. Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, et al. JD Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 1998; 281: 1677-9.
4. Woo PA, McLure KG, Lees-Miller SP, Rancourt DE, Lee PW. DNA-dependent protein kinase acts upstream of p53 in response to DNA damage. Nature 1998; 394: 700-4.
5. Iliakis G. Cell cycle regulation in irradiated and non irradiated cells. Semin Oncol 1997; 24: 602-15.
6. Martinez AM, Afshar M, Martin F, Cavadore JC, Labbe JC, Doree M. Dual phosphorylation of the T-loop in cdk7: Its role in controlling cyclin H binding and CAK activity. EMBO J 1997; 16: 343-54.
7. Morgan DO. Principles of CDK regulation. Nature 1995; 374: 131-4.
8. Elledge SJ, Harper JW. Cdk inhibitors: On the threshold of checkpoints and development. Curr Opin Cell Biol 1994; 6: 847-52.
9. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev 1995; 9: 1149-63.
10. Suzuki-Takahashi I, Kitagawa M, Saijo M, Higashi H, Ogino H, Matsumoto H, et al. The interactions of E2F with pRB and with p107 are regulated via the phosphorylation of pRB and p107 by a cyclin-dependent kinase. Oncogene 1995; 10: 1691-8.
11. Cartwright P, Muller H, Wagener C, Holm K, Helin K. E2F-6: A novel member of the E2F family is an inhibitor of E2F-dependent transcription. Oncogene 1998; 17: 611-23.
12. Kitagawa M, Higashi H, Suzuki-Takahashi I, Segawa K, Hanks SK, Taya Y, et al. Phosphorylation of E2F-1 by cyclin A-cdk2. Oncogene 1995; 10: 229-36.
13. Gu Y, Rosenblatt J, Morgan DO. Cell cycle regulation of CDK2 activity by phosphorylation of Thr160 and Tyr15. EMBO J 1992; 11: 3995-4005.
14. Jinno S, Suto K, Nagata A, Igarashi M, Kanaoka Y, Nojima H, et al. CDC25A is a novel phosphatase functioning early in the cell cycle. EMBO J 1994; 13: 1549-56.
15. Hoffman I, Draetta G, Karsenti E. Activation of the phosphatase activity of human CDC25A by a cdk2-cyclin E dependent phosphorylation at the G1/S transition. EMBO J 1994; 13: 4302-10.
16. King RW, Deshaies RJ, Peters JM, Kirschner MW. How proteolysis drives the cell cycle. Science 1996; 274: 1652-9.
17. Little JB. Delayed initiation of DNA synthesis in irradiated human diploid cclls. Nature 1968; 218: 1064-5.
18. Kasran MB, Zhan Q, El-Deiry WS, Carrier F, Jacks T, Walsh WV, et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia telangiectasia. Cell 1992; 71: 587-97.
19. Zhan Q, Carrier F, Pornace A. Induction of cellular p53 activity by DNA-damaging agents and growth arrest. Mol Cell Biol 1993; 13: 4242-50.
20. Meek DW. Post-translational modification of p53 and the integration of stress signal. Pathol Biol 1997; 45: 804-14.
21. Jin S, Inoue S, Weaver DT. Functions of the DNA dependent protein kinase. Cancer Surv 1997; 29: 221-61.
22. Poltoratsky VP, Shi X, York JD, Lieber MR, Carter TH. Human DNA-activated protein kinase (DNA-PK) is homologous to phosphatidylinositol kinases. J Immunol 1995; 155: 4529-33.
23. Lees-Miller SP, Sakaguchi K, Ullrich SJ, Appella E, Anderson CW. Human DNA-activated protein kinase phosphorylates serines 15 and 37 in the amino-terminal transactivation domain of human p53. Mol Cell Biol 1992; 12: 5041-9.
24. Soussi T, May P. Structural aspects of the p53 protein in relation to gene evolution: A second look. J Mol Biol 1996; 260: 623-37.
25. Fiscella M, Ullrich SJ, Zambrano N, Shields MT, Lin D, Lees-Miller SP, et al. Mutation of the serine 15 phosphorylation site of human p53 reduces the ability of p53 to inhibit cell cycle progression. Oncogene 1993; 8: 1519-28.
26. Fried LM, Koumenis C, Peterson SR, Green SL, van Zijl P, Allalunis-Turner J, et al. The DNA damage response in DNA-dependent protein kinase-deficient SCID mouse cells: Replication protein A hyperphos-phorylation and p53 induction. Proc Natl Acad Sci USA 1996; 93: 13825-30.
27. Rathmell WK, Kaufmann WK, Hurt JC, Byrd LL, Chu G. DNA- dependent protein kinase is not required for accumulation of p53 or cell cycle arrest after DNA damage. Cancer Res 1997; 57: 68-74.
28. Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, et al. A single ataxia telangiectasia gene with a product similar to P1-3 kinase. Science 1995; 268: 1749-53.
29. Hartley KO, Gell D, Smith GC, Zhang H, Divecha N, Connelly MA, et al. DNA-dependent protein kinase catalytic subunit: A relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product. Cell 1995; 82: 849-56.
30. Siliciano JD, Canman CE, Taya Y, Sakaguchi K, Appella E, Kastan MB. DNA damage induces phosphorylation of the amino terminus of p53. Genes Dev 1997; 11: 3471-81.
31. Barlow C, Brown KD, Deng CX, Tagle DA, Wynshaw-Boris A. ATM selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways. Nature Genet 1997; 17: 453-6.
32. Shafman T, Khanna KK, Kedar P, Spring K, Kozlov S, Yen T, et al. Interaction between ATM protein and c-Abl in response to DNA damage. Nature 1997; 387: 520-3.
33. Yuan ZM. Role of c-Abl tyrosine kinase in growth arrest response to DNA damage. Nature 1996; 382: 272-4.
34. Avila MA, Otero G, Cansado J, Dritschilo A, Velasco JA, Notario V. Activation of phospholipase D participates in signal transduction pathways responsive to gamma-radiation. Cancer Res 1993; 53: 4474-6.
35. Weichselbaum RR, Hallahan D, Fuks Z, Kufe D. Radiation induction of immediate early genes: Effectors of the radiation-stress response. Int J Radiat Oncol Biol Phys 1994; 30: 229-34.
36. Ullrich SJ, Mercer WE, Appella E. Human wild-type p53 adopts a unique conformational and phosphorylation state in vivo during growth arrest of glioblastoma cells. Oncogene 1992; 7: 1635-43.
37. Delphin C, Baudier J. The protein kinase C activator, phorbol ester, cooperates with the wild-type p53 species of Ras-transformed embryo fibroblasts growth arrest. J Biol Chem 1994; 269: 29579-87.
38. Verheij M, Ruiter GA, Zerp SF, van Blitterswijk WJ, Fuks Z, Haimovitz-Friedman A, et al. The role of the stress-activated protein kinase (SAPK/JNK) signaling pathway in radiation-induced apoptosis. Radiother Oncol 1998; 47: 225-32.
39. Milne DM, Campbell DG, Caudwell FB, Meek DW. Phosphorylation of the tumor suppressor protein p53 by mitogen-activated protein kinases. J Biol Chem 1994; 269: 9253-60.
40. Milne DM, Campbell LE, Campbell DG, Meek DW. p53 is phosphorylated in vitro and in vivo by an ultraviolet radiation-induced protein kinase characteristic of the c-Jun kinase, JNK1. J Biol Chem 1995; 270: 5511-8.
41. Dutta A, Ruppert JM, Aster JC, Winchester E. Inhibition of DNA replication factor RPA by p53. Nature 1993; 365: 79-82.
42. Gulbis JM, Kelman Z, Hurwitz J, O'Donnell M, Kuriyan J. Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA. Cell 1996; 87: 297-306.
43. Podust VN, Podust LM, Goubin F, Ducommun B, Hubscher U. Mechanism of inhibition of proliferating cell nuclear antigen-dependent DNA synthesis by the cyclin-dependent kinase inhibitor p21. Biochemistry 1995; 34: 8869-75.
44. Medema RH, Klompmaker R, Smits VA, Rijksen G. p21waf1 can block cells at two points in the cell cycle, but does not interfere with processive DNA-replication or stress-activated kinases. Oncogene 1998; 16: 431-41.
45. Zhan Q, Bae I, Kastan MB, Fornace AJ Jr. The p53-dependent gamma-ray response of GADD45. Cancer Res 1994; 54: 2755-60.
46. Smith ML, Chen IT, Zhan Q, Bac I, Chen CY, Gilmer TM, et al. Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science 1994; 266: 1376-80.
47. Smith ML, Konrny HU, Zhan Q, Sreenath A, O'Connor PM, Fornace AJ Jr. Antisense GADD45 expression results in decreased DNA repair and sensitizes cells to u.v.-irradiation or cisplatin. Oncogene 1996; 13: 2255-63.
48. Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev 1993; 7: 1126-32.
49. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature 1997; 387: 296-9.
50. Fuchs SY, Adler V, Buschmann T, Wu X, Ronai Z. Mdm2 asssociation with p53 targets its ubiquitination. Oncogene 1998; 17: 2543-7.
51. Shieh SY, Ikeda M, Taya Y, Prives C. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 1997; 91: 325-34.
52. Mayo LD, Turchi JJ, Berberich JJ. Mdm-2 phosphorylation by DNA-dependent protein kinase prevents interaction with p53. Cancer Res 1997; 57: 5013-6.
53. Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland I., Chin I., et al. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 1998; 92: 713-23.
54. Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci USA 1998; 95: 8292-7.
55. Chin L, Pomerantz J, DePinho RA. The INK4a/ARF tumor suppressor: One gene-two products-two pathways. Trends Biochem Sci 1998; 23: 291-6.
56. Martin K, Trouche D, Hagemeier C, Sorensen TS, La Thangue NB, Kauzarides P. Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein. Nature 1995; 375: 691-4.
57. Xiao ZX. Interaction between the retinoblastoma protein and the oncoprotein MDM2. Nature 1995; 375: 694-8.
58. Sandhu C, Garbe J, Bhattacharya N, Daksis J, Pan CH, Yaswen P, et al. Transforming growth factor beta stabilizes p15INK4B protein, increases p15INK4B-cdk4 complexes, and inhibits cyclin D1-cdk4 association in human mammary epithelial cells. Mol Cell Biol 1997; 17: 2458-67.
59. Reynisdottir I, Polyak K, Iavarone A, Massague J. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev 1995; 9: 1831-45.
60. Sugiyama A, Nagaki M, Shidoji Y, Moriwaki H, Muto Y. Regulation of cell cycle-related genes in rat hepatocytes by transforming growth factor beta1. Biochem Biophys Res Commun 1997; 238: 539-43.
61. Iavarone A, Massague J. Repression of the CDK activator CDC25A and cell-cycle arrest by cytokine TGF-beta in cells lacking the CDK inhibitor p15. Nature 1997; 387: 417-22.
62. Jimenez G, Yucel J, Rowley R, Subramani S. The rad3' gene of Schizosaccharomyces pombe is involved in multiple checkpoint functions and in DNA repair. Proc Natl Acad Sci USA 1992; 89: 4952-6.
63. Walworth NC, Bernards R. Rad-dependent response of the chk1- encoded protein kinase at the DNA damage checkpoint. Science 1996; 271: 353-6.
64. Peng CY, Graves PR, Thoma RS, Wu Z, Shaw AS, Piwnica-Worms H. Mitotic and G2 checkpoint control: Regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science 1997; 277: 1501-5.
65. Bentley NJ, Holtzman DA, Flaggs G, Keegan KS, DeMaggio A, Ford JC, et al. The Schizosaccharomyces pombe rad3 checkpoint gene. EMBO J 1996; 15: 6641-51.
66. Morgan SE, Kastan MB. p53 and ATM: Cell cycle, cell death, and cancer. Adv Cancer Res 1997; 71: 1-25.
67. Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, et al. Conservation of the Chk1 checkpoint pathway in mammals: Linkage of DNA damage to Cdk rcgutation through CDC25. Science 1997; 277: 1497-501.
68. Maity A, McKenna WG, Muschel RJ. Evidence for post-transcriptional regulation of cyclin B1 mRNA in the cell cycle and following irradiation in HeLa cells. EMBO J 1995; 14: 603-9.
69. Agarwal ML, Agarwal A, Taylor WR, Stark GR. p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. Proc Natl Acad Sci USA 1995; 92: 8493-7.
70. Aloni-Grinstein R, Schwartz D, Rotter V. Accumulation of wild-type p53 protein upon gamma-irradiation induces a G2 arrest-dependent immunoglobulin kappa light chain gene expression. EMBO J 1995; 14: 1392-401.
71. Guillouf C, Rosselli F, Krishnaraju K, Moustacchi E, Hoffman B, Liebermann DA. p53 involvement in control of G2 exit of the cell cycle: Role in DNA damage-induced apoptosis. Oncogene 1995; 10: 2263-70.
72. Azzam EI, de Toledo SM, Pykett MJ, Nagasawa H, Little JB. CDC2 is down-regulatcd by ionizing radiation in a p53-dependent manner. Cell Growth Differ 1997; 8: 1161-9.
73. Ohta T, Okamoto K, Isohashi F, Shibata K, Fukuda M, Yamaguchi S. et al. T-loop deletion of CDC2 from breast cancer tissues eliminates binding to cyclin B1 and cyclin-dependent kinase inhibitor p21. Cancer Res 1998; 58: 1095-8.
74. Cayrol C, Knibichler M, Ducommun B. p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells. Oncogene 1998; 16: 311-20.
75. Hermeking H, Lengauer C, Polyak K, He TC, Zhang L, Thiagalingam S, et al. 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell 1997; 1: 3-11.
76. Waterman MJ, Stavridi ES, Waterman JL, Hatazonetis TD. ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins. Nature Genet 1998; 19: 175-8.
77. Winters ZE, Ongkeko WM, Harris AL, Norbury CJ. p53 regulates Cdc2 independently of inhibitory phosphorylation to reinforce radiation-induced G2 arrest in human cells. Oncogene 1998; 17: 673-8.
78. Bischoff JR, Friedman PN, Marshak DR, Prives C, Beach D. Human p53 is phosphorylated by p60-cdc2 and cyclin B-cdc2. Proc Natl Acad Sci USA 1990; 87: 4766-70.
79. Leach SD, Scatena CD, Keefer CJ, Goodman HA, Song SY, Yang L, et al. Negative regulation of Weel expression and Cdc2 phosphorylation during p53-mediated growth arrest and apoptosis. Cancer Res 1998; 58: 3231-6.
80. Schwartz D, Almog N, Peled A, Goldfinger N, Rotter V. Role of wild type p53 in the G2 phase: Regulation of the gamma-irradiation-induced delay and DNA repair. Oncogene 1997; 15: 2597-607.
81. Lee SE, Mitchell RA, Cheng A, Hendrickson EA. Evidence for DNA-PK-dependent and -independent DNA double-strand break repair pathways in mammalian cells as a function of the cell cycle. Mol Cell Biol 1997; 17: 1425-33.
82. Han Z, Charrerjee D, He DM, Early J, Pantazis P, Wyche JH, et al. Evidence for a G2 checkpoint in p53-independent apoptosis induction by X-irradiation. Mol Cell Biol 1995; 15: 5849-57.
83. Nagasawa H, Keng P, Harley R, Dahlberg W, Little JB. Relationship between gamma-ray-induced G2/M delay and cellular radiosensitivity. Int J Radiat Biol 1994; 66: 373-9.
84. Sandell LI, Zakian VA. Loss of a yeast telomere: Arrest, recovery, and chromosome loss. Cell 1993; 75: 729-39.
85. Huang LC, Clarkin KC, Wahl GM. p53-dependent cell cycle arrests are preserved in DNA-activated protein kinase-dcficient mouse fibroblasts. Cancer Res 1996; 56: 2940-1.
86. Lane DP. Cancer. p53, guardian of the genome. Nature 1992; 358: 15-6.
87. Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 1992; 89: 7491-5.
88. Lin JY, Simmons DT. The ability of large T antigen to complex with p53 is necessary for the increased life span and partial transformation of human cells by simian virus 40. J Virol 1991; 65: 6447-53.
89. Tsang NM, Nagasawa H, Li C, Little JB. Abrogation of p53 function by transfection of HPV16 E6 gcnc enhances the resistance of human diploid fibroblasts to ionizing radiation. Oncogene 1995; 10: 2403-8.
90. Linke SP, Clarkin KC, Wahl GM. p53 mediates permanent arrest over multiple cell cycles in response to gamma-irradiation. Cancer Res 1997; 57: 1171-9.
91. Mellwrath AJ, Vascy PA, Ross GM, Brown R. Cell cycle arrests and radiosensitivity of human tumor cells lines: dependence on wild-type p53 for radiosensitivity. Cancer Res 1994; 54: 3718-22.
92. Brachman DG, Beckett M, Graves D, Haraf D, Vokes E, Weichselbaum RR. p53 mutation does not correlate with radiosensitivity in 24 head and neck cancer cell lines. Cancer Res 1993; 53: 3667-9.
93. Slichenmyer WJ, Nelson WG, Slebos RJ, Kastan MB. Loss of a p53-associated G1 checkpoint does not decrease cell survival following DNA damage. Cancer Res 1993; 53: 4164-8.
94. Weinert TA, Hartwell LH. The RaD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. Science 1988; 241; 317-22.
95. McKenna WG, Iliakis G, Weiss MC, Bernhard EJ, Muschel RJ. Increased G2 delay in radiation-resistant cell obtained by transformation of primary rat embryo cells with the oncogenes 11-ras and V-myc. Radiat Res 1991; 125: 283-7.
96. Russell KJ, Wiens LW, Demers GW, Galloway DA, Plon SE, Grondine M. Abrogation of the G2 checkpoint results in differential radiosensitization of G1 checkpoint-deficient and G1 checkpoint-competent cells. Cancer Res 1995; 55: 1639-42.
97. Powell NP, DeFranck JS, Connell P, Eogan M, Preffer F, Dombkowski D, et al, Differential sensitivity of p53(-) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. Cancer Res 1995; 55: 1643-8.
98. Bernhard EJ, Muschel RJ, Bakanauskas VJ, McKenna WG. Reducing the radiation-induced G2 delay causes HeLa cells to undergo apoptosis instead of mitotic death. Int J Radiat Biol 1996; 69: 575-84.
99. Tam SW, Schlegel R, Staurosporine overrides checkpoints for mitotic onset in BHK cells. Cell Growth Differ 1992; 3: 811-37.
100. Debuze BJ, Eder JP, Pardee AB. Phase 1 trial of escalating pentoxyfilline dose with constant dose thiotepa. Cancer Res 1990; 55: 6806-10.
101. Fan S, Smith ML, Rivet DJ 2nd, Duba D, Zhan Q, Kohn KW, et al. Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline. Cancer Res 1995; 55: 1649-54.
102. Andreassen PR, Margolis RL. 2-aminopurine overrides multiple cell cycle checkpoints in BHK cells. Proc Natl Acad Sci USA 1992; 89: 2272-6.
103. Wang Q. Fan S, Eastman A, Worland PJ, Sausville EA, O'Connor PM. UCN-01: A potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J Natl Cancer Inst 1996; 88: 956-65.
104. Okayasu R, Suetomi K, Ullrich RL. Wortmannin inhibits repair of DNA double-strand breaks in irradiated normal human cells. Radiat Res 1998; 149: 440-5.
105. Hosoi Y, Miyachi H, Matsumoto Y, Ikehara H, Komura J, Ishii K, et al. A phosphatidylinositol 3-kinase inhibitor wortmannin induces radioresistant DNA synthesis and sensitizes cells to bleomycin and ionizing radiation. Int J Cancer 1998; 78: 642-7.
106. Sarkaria JN, Tibbetts RS, Busby EC, Kennedy AP, Hill DE, Abraham RT. Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res 1998; 58: 4375-82.