Tuesday, August 30, 2005

Gene Silencing - Genotoxicity without Mutations

Another high powered mechanistic approach to chemical carcinogenesis – “Gene Silencing” - needs interpreting within the environmental paradigm. The risk assessment issue is whether mechanism suggests that directly observable carcinogenic effects, of necessity in a high dose range, persist to low dose ranges. Low dose continuity is generally accepted for “genotoxic” carcinogens – mutagenicity positive materials. Now comes “gene silencing” – an epigenetic event, but heritable.

Virtually all mutations make the gene product less effective. Mutational events cause cancer by disabling genes which make proteins or other products which prevent uncontrolled cellular growth.

The mutagenicity bioassay doesn’t target these specific genes. Instead, it takes a bacteria strain mutated to be unable to grow in a particular medium because of a disabled gene, and machine guns the genome to produce a few reverse mutants with the gene restored. Colonies growing indicate mutagenic potential of the agent, and thus somatic mutation potential.

Gene silencing chemicals would be invisible in this system.

Effectively, non-genotoxic agents should act just like genotoxic agents, advancing a step to producing a clone of uncontrolled cells which may progress to a tumor.

Carcinogenesis vol.26 no.9 pp.1481--1487, 2005

Silencing of genes by promoter hypermethylation: key event in
rodent and human lung cancer
Steven A.Belinsky1
Lung Cancer Program, Lovelace Respiratory Research Institute,
2425 Ridgecrest Drive SE, Albuquerque, NM 87108, USA
1Email: sbelinsk@LRRI.org

Transcriptional silencing by CpG island hypermethylation has become a critical component in the initiation and progression of lung cancer. The ability of pharmacologic agents to reverse promoter hypermethylation also makes it an attractive target to pursue for prevention of lung cancer. Animal models, together with studies in humans have fostered significant advances in elucidating the role of gene-specific methylation in cancer initiation and progression, the modulation of promoter methylation by carcinogen exposure and the ability to block tumor development by preventing epigenetically mediated gene silencing. These advances represent the beginning of efforts to develop a progression model for lung cancer that should aid efforts for early detection and gene targeting for therapy, and the development of preventive interventions that reverse epigenetic-mediated gene silencing.

No comments: