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Am J Physiol Renal Physiol 283: F262-F270, 2002. First published February 12, 2002; doi:10.1152/ajprenal.00261.2001
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Vol. 283, Issue 2, F262-F270, August 2002

Cell proliferation is insufficient, but loss of tuberin is necessary, for chemically induced nephrocarcinogenicity

Hae-Seong Yoon1, Terrence J. Monks1, Jeffrey I. Everitt2, Cheryl L. Walker3, and Serrine S. Lau1

1 Center for Molecular and Cellular Toxicology, Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712-1074; 2 Chemical Industry Institute for Toxicology Centers for Health Research, Research Triangle Park, North Carolina 27709-2233; and 3 Science Park-Research Division, The University of Texas M. D. Anderson Cancer Center, Smithville, Texas 78957

Although 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ; 2.5 µmol/kg ip) markedly increased cell proliferation within the outer stripe of the outer medulla (OSOM) of the kidney in both wild-type (Tsc2+/+) and mutant Eker rats (Tsc2EK/+), only TGHQ-treated Tsc2EK/+ rats developed renal tumors, indicating that cell proliferation per se was not sufficient for tumor development. Tuberin expression was initially induced within the OSOM after TGHQ treatment but was lost within TGHQ-induced renal tumors. High extracellular signal-regulated kinase (ERK) activity occurred in the OSOM of Tsc2EK/+ rats at 4 mo and in TGHQ-induced renal tumors. Cyclin D1 was also highly expressed in TGHQ-induced renal tumors. Reexpression of Tsc2 in tuberin-negative cells decreased ERK activity, consistent with the growth-suppressive effects of this tumor suppressor gene. Thus 1) stimulation of cell proliferation after toxicant insult is insufficient for tumor formation; 2) tuberin induction after acute tissue injury suggests that Tsc2 is an acute-phase response gene, limiting the proliferative response after injury; and 3) loss of Tsc2 gene function is associated with cell cycle deregulation.

Tsc2 gene; kidney; carcinogenesis; cell cycle


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