1.本論文使用肺癌細胞株為模式，自42個化學合成有機小分子，利用細胞生長速率測試 (MTT assay)，篩選出在低濃度下可以降低細胞生長速率之藥物。其中oxazoline衍生物MZ-01-059能夠有效在5 μM下降低A549細胞的生長速率。次由細胞群落分析證實MZ-01-059可以抑制癌細胞的增生。為了確認非小細胞肺癌的生長率下降是否與細胞凋亡相關，實驗再利用propidium iodide染色後DNA，進行後流式細胞分析，觀察細胞週期變化。實驗結果顯示MZ-01-059會讓具有野生型p53之細胞株A549及H460產生細胞凋亡。其中以H460細胞株較為顯著；但對不具有p53之H1299細胞，則會停滯在S及G2/M週期。另由二維流式細胞儀分析結果，確立H460肺癌細胞主要是以晚期細胞凋亡 (late apoptosis) 方式降低細胞存活率。由西方轉漬法鑑定與細胞凋亡相關的蛋白，發現MZ-01-059處理後細胞，會活化腫瘤抑制基因p53，此外也會使pro-caspase-3以及poly ADP ribose polymerase切割；而LC3-II (microtubule-associated protein 1 light chain 3) 在A549及H1299細胞株會增加，因此推斷這兩種細胞是先以細胞自噬保護細胞，再產生細胞凋亡，證實這個藥物所引發細胞凋亡與細胞自噬相關。本論文結果也顯示MZ-01-059能夠在低濃度下誘導活化在非小細胞肺癌引發不同程度的細胞凋亡，且與p53活化有關。

2.拓樸異構酶II抑制劑玫瑰樹鹼 (ellipticine) 為具有抑制癌細胞生長的抗癌藥物，本實驗室過去研究指出藥物可經由活化p53，使人類非小細胞肺癌A549細胞株凋亡。本論文持續探討細胞生長因子Akt對於p53進入細胞核的影響，研究使用轉殖p53質體至H1299的穩定細胞株 (HW16)。但當加入外源Akt會增加ellipticine對細胞生長的抑制效應，並讓sub G1週期細胞數目上升，而Akt及p53會被共同誘導移入細胞核內，DNA修補酶PARP也受到剪切。但將AktS473位點突變後，誘導產生的細胞凋亡會被抑制；而AktT308位點突變後抑制能力則較不明顯。Ellipticine所引發的細胞凋亡也與細胞自噬的形成有關，加入Akt後細胞內LC3-I轉換成LC3-II的比例增加，但當AktS473位點突變後，所誘導的細胞自噬也會降低。因此本研究顯示ellipticine所誘導產生的細胞凋亡是與Akt及p53移動至細胞核及細胞自噬形成有關，且AktS473位點的磷酸化對於藥物引發的細胞凋亡具有重要性。

1.The most common form of non-small-cell-lung-cancer (NSCLC) occurs among non-smokers in women. Because of the drug resistance, there is always a need to identify new therapeutic agents against this disease. Based on screening assay from the stock chemicals, we are identifying whether the oxazoline derivatives are potential cytotoxic drugs in human lung cancer epithelial cells through mononuclear cell direct cytotoxicity assay (MTT assay). After screening a total of more than 42 compounds, one of the synthetic chemicals (MZ-01-059), effectively suppressed growth in human adenocarcinoma in three lung cancer cell lines with different p53 genotypes, (A549 (p53+/+), H460 (p53+/+) and H1299 (p53-/-). The result was further confirmed by colony formation assay. However, the apoptotic death by (MZ-01-059) was detected only in A549 and H460 cells, but not in H1299 cells as measured by flow cytometry. The results indicated tumor suppressor p53 is essential for drug activity. In addition, MZ-01-059 activated caspase-3 and poly(ADP-ribose) polymerase cleavages in both A549 cells and H460 cells. The findings demonstrate that the candidate drug induces the anticancer effects through apoptotic cell death in A549 and H460 cells that is regulated by p53.

2.Topoisomerase II inhibitors, ellipticine and its analogues, were reported promising anticancer drugs due to its antineoplastic effects. Tumor suppressor p53 plays an important role in DNA damage-induced apoptosis. The phosphatidylinositol 3-OH-kinase-Akt pathway inhibits p53-mediated transcription and apoptosis, while the Akt substrate MDM2, an ubiquitin ligase for p53, plays a pivotal role in regulation of the stability of p53. Previously, we showed that ellipticine-induced cytotoxicity in non-small-cell-lung-cancer (NSCLC) was achieved through autophagy and apoptotic death as a result of Akt-modulation. Nucleus translocation of p53 and Akt and recruitment of autophagosome were found in A549 cells. In this study, we further demonstrated that Akt-related cell death also occurred in p53-deficient cells with stable expression of exogenous p53 ( HW16). The cell death phenotype was ameliorated when transfected with dominant-negative AKTS473A construct. On the other hand, the apoptotic phenotype was also be reverted by AktT308A with less dominant effect. Akt and p53 were both translocated into nucleus during apoptosis in ellipticine -treated HW16 cells. Our work demonstrated that Akt and p53 nuclear translocation are essential in elliptpcine- induced apoptosis in HW16 cells.

1. Abedin MJ, Wang D, McDonnell MA, Lehmann U, Kelekar A. Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death & Differentiation. 2007; 14: 500-10.

Alderden RA, Hall MD, Hamble TW. The Discovery and Development of Cisplatin. Journal of Chemical Education. 2006; 83: 728-34

Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA. Mechanism of activation of protein kinase B by insulin and IGF-1. The EMBO Journal. 1996; 15: 6541-51.

Alfonso B, Antonio DL, Vincenzo E, Mara C, Enrico P. S, and Gennaro Citro. Tumor suppressors and cell-cycle proteins in lung cancer. Pathology Research International. 2011; 2011: 605042

Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, Sasaki M, Klaus JA, Otsuka T, Zhang Z, Koehler RC, Hurn PD, Poirier GG, Dawson VL, Dawson TM. Poly(ADP-ribose) (PAR) polymer is a death signal. Proceedings of the National Academy of Sciences of the United States of America. 2006; 103: 18308-13.

Arico, S, A. Petiot, C. Bauvy, P.F. Dubbelhuis, A.J. Meijer, P. Codogno, and E. Ogier-Denis. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. The Journal of Biological Chemistry. 2001; 276: 35243–35246.

Bertwistle D, Sugimoto M, Sherr CJ. Physical and functional interactions of the Arf tumor suppressor protein with nucleophosmin/B23. Molecular and Cellular Biology. 2004; 24: 985-96.

Bunn PA Jr. Chemotherapy for advanced non-small cell lung cancer: Who, what, when, why? Journal of Clinical Oncology. 2002; 20: 23-33

Chen D, Kon N, Li M, Zhang W, Qin J, Gu W. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell. 2005; 121: 1071-83.

Chen S, Rehman SK, Zhang W, Wen A, Yao L, Zhang J. Autophagy is a therapeutic target in anticancer drug resistance. Biochimica et Biophysica Acta. 2010;1806: 220-9.

Chen Y, Klionsky DJ. The regulation of autophagy - unanswered questions. Journal of Cell Science. 2011; 124: 161-70.

Purring-Koch C, McLendon G. Cytochrome c binding to Apaf-1: The effects of dATP and ionic strength. Proceedings of the National Academy of Sciences. 2000; 97: 11928–11931.

Choi KS. Autophagy and cancer. Experimental and Molecular Medicine. 2012; 44: 109-20.

Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O, Crook T, Ryan KM. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell. 2006; 126: 121-34.

Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gélinas C, Fan Y, Nelson DA, Jin S, White E. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 2006; 10: 51-64.

Dickson, M. & Gagnon, J. P. Key factors in the rising cost of new drug discovery and development. Nature Reviews Drug Discovery. 2004; 3: 417-29

Downward J. Ras signalling and apoptosis. Current Opinion in Genetics & Development. 1998; 8: 49–54.

Edinger AL, Thompson CB. Death by design: apoptosis, necrosis and autophagy. Current Opinion in Cell Biology. 2004;16: 663-9.

Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nature Reviews Clinical Oncology. 2009; 6: 638-47

Entwistle RA, Winefield RD, Foland TB, Lushington GH, Himes RH. The paclitaxel site in tubulin probed by site-directed mutagenesis of Saccharomyces cerevisiae beta-tubulin. FEBS Letters. 2008; 582: 2467-70.

Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. British Medical Journal. 2005; 330: 1304-5.

Fan QW, Cheng C, Hackett C, Feldman M, Houseman BT, Nicolaides T, Haas-Kogan D, James CD, Oakes SA, Debnath J, Shokat KM, Weiss WA. Akt and autophagy cooperate to promote survival of drug-resistant glioma. Science Signaling. 2010;3: ra81.

Fazi B, Bursch W, Fimia GM, Nardacci R, Piacentini M, Di Sano F, Piredda L. Fenretinide induces autophagic cell death in caspase-defective breast cancer cells. Autophagy. 2008; 4:435-41.

Galano G, Caputo M, Tecce MF, Capasso A. Efficacy and tolerability of vinorelbine in the cancer therapy. Current Drug Safety. 2011; 6: 185-93.

Giam M, Huang D.C, Bouillet P. BH3-only proteins and their roles in programmed cell death. Oncogene. 2008; 27: S128-36.

Giannakakou P, Robey R, Fojo T, Blagosklonny MV. Low concentrations of paclitaxel induce cell type-dependent p53, p21 and G1/G2 arrest instead of mitotic arrest: molecular determinants of paclitaxel-induced cytotoxicity. Oncogene. 2001; 20: 3806-13.

González-Polo RA, Boya P, Pauleau AL, Jalil A, Larochette N, Souquère S, Eskelinen EL, Pierron G, Saftig P, Kroemer G. The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death. Journal of Cell Science. 2005; 118: 3091-102.

Gozuacik D, Kimchi A. Autophagy and cell death. Current Topics in Developmental Biololgy. 2007; 78: 217-45.

Hagner N, Joerger M. Cancer chemotherapy: targeting folic acid synthesis. Cancer Management and Research. 2010; 2: 293-301.

Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993; 75: 805-16.

Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997; 387: 296-9

Hsieh JL, Lu CS, Huang CL, Shieh GS, Su BH, Su YC, Lee CH, Chang MY, Wu CL, Shiau AL. Acquisition of an enhanced aggressive phenotype in human lung cancer cells selected by suboptimal doses of cisplatin following cell deattachment and reattachment. Cancer Letters. 2012; 321: 36-44.

Klionsky DJ, Cregg JM, Dunn WA Jr, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y. A unified nomenclature for yeast autophagy-related genes. Developmental Cell. 2003; 5: 539-45.

Ko LJ, Prives C. p53: puzzle and paradigm. Current Opinion in Genetics & Development 1996; 10: 1054-72.

Lane DP. Cancer. p53, guardian of the genome. Nature. 1992; 358: 15-6.

Lee JA. Autophagy in neurodegeneration: two sides of the same coin. Biochemistry and Molecular Biology Reports. 2009; 42: 324-30.

Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997; 91: 479-89.

Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide3-kinase pathway in cancer. Nature Reviews Drug Discovery. 2009; 8: 627–644.

Liu X, Zou H, Slaughter C, Wang X. Dff, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell. 1997; 89: 175–184

Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nature Reviews Molecular Cell Biology. 2007; 8: 741-52.

Masters SC, Yang H, Datta SR, Greenberg ME, Fu H. 14-3-3 inhibits Bad-induced cell death through interaction with serine-136. Molecular Pharmacology. 2001; 60: 1325-31.

Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008; 451: 1069-75.

Purring-Koch C and McLendon G. Cytochrome c binding to Apaf-1: the effects of dATP and ionic strength. Proceedings of the National Academy of Sciences of the United States of America. 2000; 97: 11928-31.

Pyo JO, Jang MH, Kwon YK, Lee HJ, Jun JI, Woo HN, Cho DH, Choi B, Lee H, Kim JH, Mizushima N, Oshumi Y, Jung YK. Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. The Journal of Biological Chemistry. 2005; 280: 20722-9.

Schinzel A, Kaufmann T, Borner C. Bcl-2 family members: integrators of survival and death signals in physiology and pathology. Biochimica et Biophysica Acta. 2004; 1644: 95-105

Sengupta S, Tyagi P, Velpandian T, Gupta YK, Gupta SK. Etoposide encapsulated in positively charged liposomes: pharmacokinetic studies in mice and formulation stability studies. Pharmacol Research. 2000; 42: 459-64.

Sharpless NE, DePinho RA. Telomeres, stem cells, senescence, and cancer. The Journal of Clinical Investigation. 2004; 113: 160-8.

Sheikh MS, Fornace AJ Jr. Role of p53 family members in apoptosis. Journal of Cellular Physiology. 2000; 182: 171-81.

Sherr CJ. D-type cyclins. Trends in Biochemical Sciences. 1995; 20: 187-90.

Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB, Tsujimoto Y. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nature Cell Biology. 2004; 6: 1221-8.

Slebos RJ, Lee MH, Plunkett BS, Kessis TD, Williams BO, Jacks T, Hedrick L, Kastan MB, Cho KR. p53-dependent G1 arrest involves pRB-related proteins and is disrupted by the human papillomavirus 16 E7 oncoprotein. Proceedings of the National Academy of Sciences of the United States of America. 1994; 91: 5320-4.

Smith DM, Patel S, Raffoul F, Haller E, Mills GB, Nanjundan M. Arsenic trioxide induces a beclin-1-independent autophagic pathway via modulation of SnoN/SkiL expression in ovarian carcinoma cells. Cell Death & Differentiation. 2010;17: 1867-81.

Srivastava M, Bubendorf L, Srikantan V, Fossom L, Nolan L, Glasman M, Leighton X, Fehrle W, Pittaluga S, Raffeld M, Koivisto P, Willi N, Gasser TC, Kononen J, Sauter G, Kallioniemi OP, Srivastava S, Pollard HB. ANX7, a candidate tumor suppressor gene for prostate cance. Proceedings of the National Academy of Sciences of the United States of America. 2001; 98: 4575-80.

Tidow H , Melero R , Mylonas E , Freund SMV , Grossmann JG , Carazo JM , Svergun DI , Valle M , Fersht AR. Quaternary structures of tumor suppressor p53 and a specific p53–DNA complex. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104: 12324–12329.

Ute M. Moll1 and Oleksi Petrenko. The MDM2-p53 interaction. Molecular Cancer Research. 2003; 1: 1001-8.

Van Duin M, Woolson H, Mallinson D, Black D. Genomics in target and drug discovery. Biochemical Society Transactions. 2003; 31: 429-32.

Vaux DL. Apoptogenic factors released from mitochondria. Biochimica et Biophysica Acta. 2010;1813: 546-50.

Veronesi A, Magri MD, Tirelli U, Carbone A, Mazza F, Franceschi S, Talamini R, Ardizzoni A, Canobbio L, Rosso R. Chemotherapy of advanced non-small-cell lung cancer with cyclophosphamide, adriamycin, methotrexate, and procarbazine versus cisplatin and etoposide. A randomized study. American Journal of Clinical Oncology. 1988; 11: 566-71.

Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000; 408: 307-10.

Wu CC, Li TK, Farh L, Lin LY, Lin TS, Yu YJ, Yen TJ, Chiang CW, Chan NL. Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide. Science. 2011; 333: 459-62.

Yang H, Wen YY, Zhao R, Lin YL, Fournier K, Yang HY, Qiu Y, Diaz J, Laronga C, Lee MH. DNA damage-induced protein 14-3-3 sigma inhibits protein kinase B/Akt activation and suppresses Akt-activated cancer. Cancer Research. 2006; 66: 3096-105.

Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Molecular Cancer Therapeutics. 2011; 10:1533-41.

Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, Brunner T, Simon HU. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nature Cell Biology. 2006; 8: 1124-32.

台灣癌症防治網, Taiwan Clinical Oncology Research Foundation. http://cisc.twbbs.org/

2.
Acton EM, Narayanan VL, Risbood PA, Shoemaker RH, Vistica DT, and Boyd MR. Anticancer specificity of some ellipticinium salts against human brain tumors in vitro. Journal of Medicinal Chemistry. 1994; 37: 2185–9.

Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, and Hemmings BA. Mechanism of activation of protein kinase B by insulin and IGF-1. The EMBO Journal. 1996; 15: 6541–51.

Biondi M. R. and Nebreda R. A. Signaling specificity of Ser/Thr protein kinases through docking-site-mediated interactions. Biochemical Journal. 2003; 372: 1-13.

Braybrooke JP, Levitt NC, Joel S, Davis T, Madhusudan S, Turley H, Wilner S, Harris AL, and Talbot DC. Pharmacokinetic study of cisplatin and infusional etoposide phosphate in advanced breast cancer with correlation of response to topoisomerase II alpha expression. Clinical Cancer Research 2003; 9: 4682-88.

Brodbeck D, Cron P, Hemmings BA. A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain. The Journal of Biological Chemistry. 1999; 274: 9133-6.

Chène P. Inhibiting the p53-MDM2 interaction: an important target for cancer therapy. Nature Reviews Cancer. 2003; 3: 102-9.

Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes & Development. 1998; 12: 3499-511.

Dimmeler S, Zeiher AM. AKT takes center stage in angiogenesis signaling. Circulation Research. 2000; 86: 4-5.

Downward J. Ras signalling and apoptosis. Current Opinion in Genetics & Development. 1998; 8: 49-54.

Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Reviews Cancer. 2009; 9: 550-62.

Eymin B, Gazzeri S, Brambilla C, Brambilla E. Mdm2 overexpression and p14(ARF) inactivation are two mutually exclusive events in primary human lung tumors. Oncogene. 2002; 21: 2750-61.

Fang K, Chen SP, Lin CW, Cheng WC, and Huang HT. Ellipticine-induced apoptosis depends on AKT translocation and signaling in lung epithelial cancer cells. Lung Cancer 2009; 63: 227-34.

Feng J, Tamaskovic R, Yang Z, Brazil DP, Merlo A, Hess D, Hemmings BA. Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation. The Journal of Biological Chemistry. 2004; 279: 35510-7.

Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997; 387: 296-9.

Ko LJ, Prives C. p53: puzzle and paradigm. Genes & Development. 1996; 10: 1054-72.

Kuo PL, Hsu YL, Chang CH, and Lin CC. The mechanism of ellipticine-induced apoptosis and cell cycle arrest in human breast MCF-7 cancer cells. Cancer Letters 2005; 223: 293–301.

Kuo YC, Kuo PL, Hsu YL, Cho CY, Lin CC. Ellipticine induces apoptosis through p53-dependent pathway in human hepatocellular carcinoma HepG2 cells. Life Sciences. 2006; 78: 2550-7.

Leite KR, Franco MF, Srougi M, Nesrallah LJ, Nesrallah A, Bevilacqua RG, Darini E, Carvalho CM, Meirelles MI, Santana I, Camara-Lopes LH. Abnormal expression of MDM2 in prostate carcinoma. Modern Pathology. 2001; 14: 428-36.

Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nature Reviews Drug Discovery. 2009; 8: 627-44.

Michell BJ, Griffiths JE, Mitchelhill KI, Rodriguez-Crespo I, Tiganis T, Bozinovski S, de Montellano PR, Kemp BE, Pearson RB. The AKT kinase signals directly to endothelial nitric oxide synthase. Current Biology. 1999; 9: 845-8.
Moll UM, Petrenko O. The MDM2-p53 interaction. Molecular Cancer Research. 2003; 1: 1001-8.

Monnot M, Mauffret O, Simon V, Lescot E, Psaume B, and Saucier J. M. DNA-drug recognition and effects on topoisomerase II-mediated cytotoxicity: A three-mode binding model for ellipticine derivatives. The Journal of Biological Chemistry. 1991; 266: 1820-9

Peng Y, Li C, Chen L, Sebti S, Chen J. Rescue of mutant p53 transcription function by ellipticine. Oncogene. 2003; 22: 4478-87.

Riou JF, Gabillot M, Philippe M, Schrevel J, Riou G. Purification and characterization of Plasmodium berghei DNA topoisomerases I and II: drug action, inhibition of decatenation and relaxation, and stimulation of DNA cleavage. Biochemistry. 1986; 25: 1471-9.

Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005; 307: 1098-101.

Schon O, Friedler A, Bycroft M, Freund SM, Fersht AR. Molecular mechanism of the interaction between MDM2 and p53. Journal of Molecular Biology. 2002; 323: 491-501.

Sharpless NE, DePinho RA. Telomeres, stem cells, senescence, and cancer. The Journal of Clinical Investigation. 2004; 113: 160-8.

Stiborova M, Rupertova M, Schmeiser HH, Frei E. Molecular mechanisms of antineoplastic action of an anticancer drug ellipticine. Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czech Republic. 2006; 150: 13-23.

Tonks NK, Myers MP. Structural assets of a tumor suppressor. Science. 1999; 286: 2096-7.

Tsurutani J, Fukuoka J, Tsurutani H, Shih JH, Hewitt SM, Travis WD, Jen J, Dennis PA. Evaluation of two phosphorylation sites improves the prognostic significance of Akt activation in non-small-cell lung cancer tumors. Journal of Clinical Oncology. 2006; 24: 306-14.

Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nature Cell Biology. 2007; 9: 316-23.

Xu GW, Mawji IA, Macrae CJ, Koch CA, Datti A, Wrana JL, Dennis JW, Schimmer AD. A high-content chemical screen identifies ellipticine as a modulator of p53 nuclear localization. Apoptosis. 2008; 13: 413-22.