Relationship Between Autophagy and Tumorigenesis

ISSN 1007-7626 CN 11-3870 / Q 2010 11 Chinese Journal of Biochemistry and Molecular Biology 26 11 988 ~ 997 * 100191 autophagy p53 Beclin 1 FoxO mtor p53 Q26 R730 Relationship Between Autophagy and Tumorigenesis WANG ChongZHANG PingZHU Wei-Guo * Department of Biochemistry and Molecular BiologyPeking University Health Science CenterBeijing 100191China Abstract Autophagy is a highly conserved catabolic process that degrades a bulk of misfolded or damaged proteins and organelles In normal cellsautophagy functions primarily to maintain the cellular homeostasis and is responsible for the regulation of organelle turnover In response to various cellular stressesautophagy plays a crucial role in preventing the accumulation of damaged proteins and organelles which are toxic and carcinogenic Howeverautophagy can promote tumor growth once the tumors are formed by supplying nutrition and energy to tumors Thus autophagy exhibits the effects of a double-blade sword in cancerswhere most tumor suppressors act as inducers of autophagy and oncogenes play inhibitory roles in autophagy Yet an exceptional case has been reported-tumor suppressor p53 suppresses the induction of autophagy in the cytoplasm In this reviewwe focus on the discussion about the relationship between autophagy and tumor development Key words autophagy cancer Beclin 1 FoxO mtor p53 1 ~ 6 7 3 macroautophagy microautophagy 2010-07-26 2010-09-20 No 31070691 chaperone-mediated * Tel 010-82802235 E-mail zhuweiguo@ bjmu edu cn Received July 26 2010 Accepted September 20 2010 Supported by National Natural Science Foundation of China No 31070691 autophagy 48 * Corresponding author E-mail zhuweiguo@ bjmu edu cn Tel 010-82802235

11 989 Beclin 1 29 Beclin 1 30 9 ~ 11 12 ~ 15 30 31 16 ~ 18 19 20 32 33 21 30 30 34 pre-autophagosomal structure 35 ~ PAS 18 Atg 38 2 Atg12-Atg5 Atg8-PE 39 Atg12-Atg5-Atg16 Atg8-PE 21 40 Atg12-Atg5 E1 Atg7 41 Atg7 Atg12 Atg12 E2 22 Atg10 42 Atg5 Atg16 Atg12-Atg5 Atg12-Atg5-Atg16 43 Atg12-Atg5-Atg16 DNA 23 Atg5 HCT116 Atg5 24 ~ 27 Atg5 LC3-Ⅱ 44 Atg8-PE Atg4 Atg4 28 Atg8 C E1

990 26 Atg7 Atg8 Atg8 40% ~ 75% Atg3 Atg3 Atg8 PE Atg8-PE 4546 Fig 1 Two ubiquitin-like conjugation systems in the process of forming pre-autophagosomal structure 47 Beclin 1 Fig 1 Beclin 1 Beclin 1 5253 Beclin 1 Beclin 1 Beclin 1 BH3 CCD ECD PI3K3C 54 PI3K3C HT- 29 55 PI3K3C 56 Beclin 1 Beclin 1 / PI3K3C Fig 2 Beclin 1-PI3K3C 3 Atg8 GATE- 16 GABARAP MAP1LC3 22 48 LC3 Fig 2 The interaction between beclin 1 / PI3K3C and 1 other important regulators in autophagy 5257 58 44 Beclin 1 and PI3K3C form the complex via CCD and ECD 1 LC3 ProLC3 motifand interacts with Bcl-2 via BH3 motif UVRAG and LC3-Ⅰ barkor are antagonists binding to the CCD motif of beclin 1 PE Bif-1 interacts with beclin 1 via UVRAG LC3-Ⅱ LC3- Beclin 1 BH3 Ⅱ 4449 LC3-Ⅱ Bcl-2 59 Bcl-2 Bcl-2 LC3-Ⅱ Beclin 1 Bcl-2 50 p62 LC3 BH3 Beclin 1 Bcl-2 Beclin 1 Bcl-2 51 p62 Beclin 1 Bcl-2 57 1 UVRAG UV radiation resistance-associated gene 1 1 Beclin 1 protein Beclin 1 Atg6 / Vps30 UVRAG 54 UVRAG Bcl-2 32 UVRAG

11 991 beclin 1 CCD Beclin 1 PI3K3C PI3K3C FoxO 60 UVRAG FoxO FoxO FoxO DNA UVRAG Bif-1 Bax-interacting factor 1 Bax Bif-1 FoxO DNA UVRAG Beclin 1 PI3K3C FoxO 61 Bif-1 Bif-1 64 32 Beclin 1 UVRAG Bif-1 Sengupta FoxO3 Atg12 LC3 Gabarapl 1 FxoO3 65 FoxO3 Beclin 1 UVRAG Bif-1 FoxO3 LC3 Ambra1 activating molecule in beclin 1- regulated antophagy Beclin 1 LC3 Bnip3 23 Ambra1 FoxO3 Mammucari 66 54 FoxO3 Bnip3 Bnip3l Sun 58 FoxO3 Barkor Beclin 1-associated autophagy- related key Bnip3 regulator Beclin 1 FoxO3 Bnip3 Beclin 1 / PI3K3C Beclin 1 PI3K / Akt FoxO FoxO LC3 FoxO3 Bnip3 Bnip3l Barkor Barkor UVRAG FoxO3 Beclin 1 Barkor Zhao 6768 FoxO1 1 2 FoxO FoxO FoxO1 FoxO1 SRIT2 FoxO1 FoxO 4 FoxO1 Atg7 FoxO1 FoxO3 FoxO4 FoxO6 63 FoxO1

992 26 mtor mtor 2 / 11 mtor mammalian target of rapamycin LKB1 mtor LKB1 PARP-1 Poly ADP-ribose T polymerase-1 PARP-1 DNA 69 75 LKB1 AMPK AMPK TSC2 TSC2 mtor mtor TSC2 Rheb GAP mtor 71 70 mtor mtor mtor Raptor mlst8 PRAS40 mtor mtor 1 mtorc1 Rictor msin1 Protor-1 mtor 2 mtorc2 mtor eif3 mtor mtorc1 eif3 S6K1 mtor p70 ribosomal protein S6 kinase 1 4EBP1 eif4e binding protein 1 S6K1 4EBP1 mtor eif3 mtor Akt 4EBP1 Akt c- 69 Andrea MycVEGFODCcyclin D1HIF-1 Mcl-1 71 Rheb mrna mtorc2 Akt473 Akt Rheb 76 Akt TSC2 TSC1 Rheb 72 mtor LKB1 mtor 69 mtor mtor LKB1 71 PI3K / Akt AMPK MAPK / ERK PI3K / AMPK Akt mtor AMPK 77 PI3K / Akt mtor TSC1 TSC2 PI3K / Akt TSC1 / TSC2 Rheb mtor 78 26 PTEN PI3K PTEN PI3K PI3K mtor 73 Cowden Bannayan-Riley-Ruvalcaba mtorc1 PRAS40 Lhermitte-Duclos Proteus 69 PRAS49 Akt PRAS40 mtor 74 mtor mtor mtor mtor Peutz-Jeghers PTEN 14-3-3 mtorc1 79 PTEN

11 993 mtor 4EBP1 mtor mtor mtor Fig 3 The role of p53 in the cytoplasm and nucleus Degtyarev 80 Akt p53 85 LKB1 p27 28 p53 p70s6k 81 mtor 78 3 p53 p53 85 p53 50% p53 p53 AMPK p53 p53 AMPK β1 β2 TSC2 p53 Sestrins 1 2 Sestrins 1 2 86 ~ p53 AMPK 88 AMPK TSC2 mtor mtor p53 MDM2 p14 ARF MDM2 MDM2 p53 p53 89 p14 ARF p53 90 Bax Bcl-2 Bcl-X L 1 p53 p53 Fig 3 p73 91 p53 p73 Atg p53 92 p53 p53 p53 p53 DNA p53 85 82 p53 - / - p53 p53 8384 8385 85 p53 p53 p53 3 mtor AMPK

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