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Isolation of cDNAs representing dithiolethione-responsive genes
T Primiano1, J A Gastel, T W Kensler
1The Department of Environmental Health Sciences, The Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205, USA.
Carcinogenesis
|November 1, 1996
Summary
1,2-dithiole-3-thione (D3T) activates cellular defense genes, including novel ones like DIG-1 and DIG-2, to inhibit carcinogen-induced tumors. This study identifies new detoxification genes and regulatory mechanisms involved in cancer prevention.
Area of Science:
- Biochemistry
- Molecular Biology
- Toxicology
Background:
- Dithiolethiones are known to inhibit tumorigenesis induced by various carcinogens.
- This inhibition is linked to the induction of carcinogen detoxification enzymes.
- Novel inducible detoxification genes remain to be identified.
Purpose of the Study:
- To identify novel genes induced by 1,2-dithiole-3-thione (D3T) that are involved in detoxification.
- To understand the regulatory mechanisms of D3T-inducible genes.
Main Methods:
- A cDNA library was created from the liver of rats treated with D3T.
- Differential hybridization was used to screen the library.
- Known and novel D3T-inducible genes were identified and their mRNA levels analyzed.
Main Results:
- Several known detoxification genes (epoxide hydrolase, aflatoxin B1-aldehyde reductase, quinone reductase, glutathione S-transferase subunits) were isolated.
- Novel genes, including ferritin subunits, ribosomal proteins (L18a, S16), and two new genes (DIG-1, DIG-2), were identified.
- mRNA levels showed 2- to 31-fold induction, with distinct kinetics suggesting at least two sets of responsive genes.
Conclusions:
- D3T induces a pleiotropic cellular defense response involving both known and novel genes.
- The identified genes, including DIG-1 and DIG-2, likely participate in inhibiting chemically induced tumorigenesis.
- Differential gene expression suggests complex regulatory mechanisms govern the response to D3T.