Cell Proliferation is Insufficient but Loss of Tuberin is Necessary for Chemical-Induced Nephrocarcinogenicity in the Eker Rat

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 Tsc-2 and Tsc-2 rats, only TGHQ-treated Tsc-2 rats developed renal tumors, indicating that cell proliferation per se was not sufficient for tumor development. Tuberin expression was initially induced within the OSOM following TGHQ treatment, but was lost within TGHQ-induced renal tumors. High extracellular signal-regulated kinase (ERK) activity occured in the OSOM of Tsc-2 rats at four months, and in TGHQ-induced renal tumors. Cyclin D1 was also highly expressed in TGHQ-induced renal tumors. Reexpression of Tsc-2 in tuberin-negative cells decreased ERK activity, consistent with the growth suppressive effects of this tumor suppressor gene. Thus (1) stimulation of cell proliferation following toxicant insult is insufficient for tumor formation; (2) tuberin induction following acute tissue injury suggests that Tsc-2 is an acute-phase response gene, limiting the proliferative response after injury and; (3) loss of Tsc-2 gene function is associated with cell cycle deregulation.