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ToxSci Advance Access originally published online on May 28, 2007
Toxicological Sciences 2007 99(1):43-50; doi:10.1093/toxsci/kfm138
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The Putative Tumor Suppressor Tsc-22 is Downregulated Early in Chemically Induced Hepatocarcinogenesis and may be a Suppressor of Gadd45b

Mari Iida*,1,2, Colleen H. Anna*, Nicole D. Gaskin*, Nigel J. Walker{dagger} and Theodora R. Devereux*

* Laboratory of Molecular Carcinogenesis {dagger} Toxicology Operations Branch, Environmental Toxicology Program, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, North Carolina 27709

1 To whom requests for reprints should be addressed at Department of Pathology, Biosafety Research Center, Foods, Drugs and Pesticides, 582-2 Shioshinden, Iwata-shi, Shizuoka 437-1213, Japan. Fax: +81-538-58-1343. E-mail: kotorogzo{at}yahoo.co.jp.

Received February 25, 2007; accepted May 16, 2007


  Abstract

Tsc-22 is a novel tumor suppressor gene that represents a new class of transcription factors that has transcriptional repressor activity. We found Tsc-22 downregulation in livers from B6C3F1 mice following treatment for 2 weeks with carcinogenic doses of the antianxiety drug oxazepam (2500 ppm) or the peroxisome proliferator Wyeth-14,643 (500 ppm) but not with two other carcinogens such as o-nitrotoluene or methyleugenol or three noncarcinogens including p-nitrotoluene, eugenol, or acetaminophen. The expression of Tsc-22 was also repressed in B6C3F1 mouse liver tumors that were induced by several chemicals from 2-year carcinogenicity studies as well as in spontaneous liver tumors. To identify potential Tsc-22 target genes in mouse liver, we transfected small interference RNA (SiRNA) designed to inhibit Tsc-22 into murine liver BNL-CL.2 cells. We selected two potential transcriptional targets of Tsc-22, growth arrest and DNA damage–inducible gene 45 ß (Gadd45b) and leucine zipper, putative tumor suppressor 2 (Lzts2) to test based on our previous complementary DNA microarray studies, showing that expression of these cancer-associated genes was increased when Tsc-22 was repressed. SiRNA treatment of BNL-CL.2 cells with Tsc-22 oligonucleotides but not nonspecific oligonucleotides decreased RNA and protein expression of Tsc-22 by 80–90%, while expression of Gadd45b gene, but not Lzts2, was increased over time after an initial decrease. Treatment of these cells with oxazepam for 48 h also resulted in decreased Tsc-22 and increased Gadd45b expression. These data provide evidence that Tsc-22 is a suppressor of Gadd45b expression, which may contribute to an early antiapoptotic response.

Key Words: Non-genotoxic; tumor suppressor gene; SiRNA.

2 Present address: Department of Pathology, Biosafety Research Center, Foods, Drugs and Pesticides, Shizuoka 437-1213, Japan.


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