Differential regulation of p21waf-1/cip-1 and Mdm2 by etoposide: etoposide inhibits the p53-Mdm2 autoregulatory feedback loop.
作者： Emma L Arriola , Ana Rodriguez Lopez , Christine M Chresta
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摘要: The Mdm2 protein is frequently overexpressed in human non-seminomatous germ cell tumours and transitional carcinoma of the bladder where it may contribute to tolerance wtp53. forms an autoregulatory feedback loop with p53; gene responsive transactivation by p53 once synthesized terminates response. We show here that topoisomerase poison etoposide, like ultra violet irradiation, inhibits synthesis. Cytotoxic concentrations etoposide (IC90 for >3 h) result inhibition induction at both RNA level. Rapid apoptosis ensues. Global transcription not inhibited: p21waf-1/cip-1 GADD45 expression increase a dose dependent manner. Inhibition synthesis depends on continuous presence suggesting DNA damage prevent transcription. Downregulation transcript occurs cells expressing HPV16-E6 p53-independent. When are treated pulse (1 h) reincubated drug free medium, commences immediately after repaired (3 h) response attenuated. Induction loss clonogenicity 3 – 5-fold lower under treatment conditions. This first observation following (topo II) poisons, feature be useful tumour types tolerated overexpression Mdm2.
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sci-hub.se 参考文章(48)
Jonathan D. Oliner, Jennifer A. Pietenpol, Sam Thiagalingam, Jeno Gyuris, Kenneth W. Kinzler, Bert Vogelstein, Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53 Nature. ,vol. 362, pp. 857- 860 ,(1993) , 10.1038/362857A0
U Knippschild, D M Milne, L E Campbell, A J DeMaggio, E Christenson, M F Hoekstra, D W Meek, p53 is phosphorylated in vitro and in vivo by the delta and epsilon isoforms of casein kinase 1 and enhances the level of casein kinase 1 delta in response to topoisomerase-directed drugs Oncogene. ,vol. 15, pp. 1727- 1736 ,(1997) , 10.1038/SJ.ONC.1201541
Roberta Montes de Oca Luna, Daniel S. Wagner, Guillermina Lozano, Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53 Nature. ,vol. 378, pp. 203- 206 ,(1995) , 10.1038/378203A0
Stuart G. Lutzker, Arnold J. Levine, A functionally inactive p53 protein in teratocarcinoma cells is activated by either DNA damage or cellular differentiation. Nature Medicine. ,vol. 2, pp. 804- 810 ,(1996) , 10.1038/NM0796-804
Arnold J. Levine, The p53 protein and its interactions with the oncogene products of the small DNA tumor viruses Virology. ,vol. 177, pp. 419- 426 ,(1990) , 10.1016/0042-6822(90)90505-L
Sheau-Yann Shieh, Masako Ikeda, Yoichi Taya, Carol Prives, DNA Damage-Induced Phosphorylation of p53 Alleviates Inhibition by MDM2 Cell. ,vol. 91, pp. 325- 334 ,(1997) , 10.1016/S0092-8674(00)80416-X
Robert Weinberg, Tumor suppressor genes Neuron. ,vol. 11, pp. 191- 196 ,(1993) , 10.1016/0896-6273(93)90177-S
Zhi-Xlong Xiao, Jiandong Chen, Arnold J. Levine, Nazanlne Modjtahedi, Jun Xing, William R. Sellers, David M. Livingston, Interaction between the retinoblastoma protein and the oncoprotein MDM2 Nature. ,vol. 375, pp. 694- 698 ,(1995) , 10.1038/375694A0
X Lu, Differential induction of transcriptionally active p53 following UV or ionizing radiation : defects in chromosome instability syndromes ? Cell. ,vol. 75, pp. 765- 778 ,(1993) , 10.1016/0092-8674(93)90496-D
Stephen N. Jones, Amy E. Roe, Lawrence A. Donehower, Allan Bradley, Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53 Nature. ,vol. 378, pp. 206- 208 ,(1995) , 10.1038/378206A0