Transformation of kidney epithelial cells by a quinol thioether via inactivation of the tuberous sclerosis‐2 tumor suppressor gene

Molecular Carcinogenesis - Tập 31 Số 1 - Trang 37-45 - 2001
Hae‐Seong Yoon1, Terrence J. Monks1, Cheryl Lyn Walker2, Serrine S. Lau1
1Center for Molecular and Cellular Toxicology, Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Texas
2The University of Texas M. D. Anderson Cancer Center, Science Park–‐Research Division, Smithville, Texas

Tóm tắt

AbstractAlthough hydroquinone (HQ) is a rodent carcinogen, because of its lack of mutagenicity in standard bacterial mutagenicity assays it is generally considered a nongenotoxic carcinogen. 2,3,5‐Tris‐(glutathion‐S‐yl)HQ (TGHQ) is a potent nephrotoxic metabolite of HQ that may play an important role in HQ‐mediated nephrocarcinogenicity. TGHQ mediates cell injury by generating reactive oxygen species and covalently binding to tissue macromolecules. We determined the ability of HQ and TGHQ to induce cell transformation in primary renal epithelial cells derived from the Eker rat. Eker rats possess a germline inactivation of one allele of the tuberous sclerosis‐2 (Tsc‐2) tumor suppressor gene that predisposes the animals to renal cell carcinoma. Treatment of primary Eker rat renal epithelial cells with HQ (25 and 50 μM) or TGHQ (100 and 300 μM) induced 2‐ to 4‐fold and 6‐ to 20‐fold increases in cell transformation, respectively. Subsequently, three cell lines (The QT‐RRE 1, 2, and 3) were established from TGHQ‐induced transformed colonies. The QT‐RRE cell lines exhibited a broad range of numerical cytogenetic alterations, loss of heterozygosity at the Tsc‐2 gene locus, and loss of expression of tuberin, the protein encoded by the Tsc‐2 gene. Only heterozygous (Tsc‐2EK/+) kidney epithelial cells were susceptible to transformation by HQ and TGHQ, as wild‐type cells (Tsc‐2+/+) showed no increase in transformation frequency over background levels following chemical exposure. These data indicate that TGHQ and HQ are capable of directly transforming rat renal epithelial cells and that the Tsc‐2 tumor suppressor gene is an important target of TGHQ‐mediated renal epithelial cell transformation. © 2001 Wiley‐Liss, Inc.

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Tài liệu tham khảo

10.1126/science.8052857

10.1016/0278-6915(92)90075-V

10.1111/j.1349-7006.1991.tb01783.x

10.1289/ehp.97105s4875

10.1080/10408449991349221

10.2307/3429556

10.1080/009841096161915

10.1002/1097-0142(19950515)75:10<2552::AID-CNCR2820751023>3.0.CO;2-1

Tavani A, 1997, Epidemiology of renal‐cell carcinoma, J Nephrol, 10, 93

10.1080/15287398509530777

10.1289/ehp.93100293

10.1016/0300-483X(80)90055-4

10.1016/0165-1218(85)90007-2

10.1016/S0165-1218(96)90118-4

10.1016/0165-1218(81)90072-0

10.1016/S0027-5107(96)00196-0

10.1016/0304-3835(92)90088-D

10.1038/bjc.1998.492

10.3109/00498259209051867

10.1016/0378-4274(93)90052-Y

10.1007/s004320050260

10.1016/0041-008X(90)90100-9

10.1093/carcin/18.12.2393

10.1021/tx000161g

10.1021/tx990160s

10.1007/978-1-4757-9480-9_35

Jeong JK, 1999, Quinol‐glutathione conjugate‐induced mutation spectra in the supF gene replicated in human AD293 cells and bacterial MBL50 cells, Cancer Res, 59, 3641

10.1021/tx9801357

10.1038/189858b0

10.1126/science.1553556

10.1038/ng0195-70

10.1006/bbrc.1994.2324

10.1073/pnas.91.24.11413

10.1073/pnas.90.17.8038

10.1111/j.1349-7006.1993.tb02808.x

10.1016/S0022-5347(17)37087-8

10.1016/0304-3835(94)90307-7

Everitt JI, 1995, Rodent model of reproductive tract leiomyomata. Clinical and pathological features, Am J Pathol, 146, 1556

10.1016/0378-4274(95)03506-0

10.1111/j.1349-7006.1995.tb03092.x

10.1038/ng0294-193

10.1002/mc.2940140107

Kubo Y, 1994, Allelic loss at the predisposing gene locus in spontaneous and chemically induced renal cell carcinomas in the Eker rat, Cancer Res, 54, 2633

10.1073/pnas.93.17.9154

10.1006/bbrc.1996.0183

10.1093/carcin/13.1.25

10.1093/carcin/15.10.2183

Lau SS, 1988, Sequential oxidation and glutathione addition to 1,4‐benzoquinone: correlation of toxicity with increased glutathione substitution, Mol Pharmacol, 34, 829

10.1016/S0140-6736(71)90287-X

10.1007/BF00285214

10.1016/S0378-4274(99)00278-7

10.1016/0027-5107(95)00125-5

10.1097/00005392-199707000-00085

10.1002/(SICI)1097-0215(19980911)77:6<895::AID-IJC16>3.0.CO;2-0

10.1172/JCI7319

Kobayashi T, 1999, Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ‐line Tsc2 mutation in mice, Cancer Res, 59, 1206

10.1074/jbc.270.27.16409

10.1074/jbc.272.46.29301

10.1073/pnas.95.26.15653

10.1074/jbc.271.3.1258

10.1074/jbc.273.23.14533

10.1038/33451

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Molecular Carcinogenesis

Tập 31 Số 1

37-45

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