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Regulation of cellular genotoxic response

By Ritu Rana
October 2010

Yoshiaki Tsuji, Ph.D., Cell biologist
Guest lecturer Yoshiaki Tsuji heads a group at N.C. State University that explores molecular mechanisms by which cellular susceptibility to cytotoxic agents and stresses are determined in normal and cancer cells. (Photo courtesy of Steve McCaw)

Principal investigators and fellows at a lunchtime presentations
Principal investigators and fellows gather each month for the lunchtime presentations in the NIEHS Executive Conference Room. (Photo courtesy of Steve McCaw)

Cell biologist Yoshiaki Tsuji, Ph.D., shared his new findings on the ways genotoxic stresses perturb cellular signaling pathways, contribute to toxicity, and influence disease outcomes in a talk Sept. 7 at NIEHS. His discussion of the transcriptional regulation of antioxidant genes by homeodomain-interacting protein kinase 2 (HIPK2) was the latest presentation in the monthly Receptor Mechanisms Discussion Group seminar series.

Tsuji is an associate professor in the Department of Environmental and Molecular Toxicology at North Carolina State University. His laboratory's main research interest is understanding how oxidative stress affects genomic integrity and iron homeostasis of cells and how this stress is implicated in neurodegenerative diseases. In addition to funding from NIH research project and supplement grants, Tsuji's work supports the research projects of several trainees in the NIEHS training grant ( managed by Health Scientist Administrator Carol Shreffler, Ph.D.

As Tsuji explained, iron plays an essential role in many cellular functions, but excess iron is potentially harmful because it can catalyze the formation of reactive oxygen species (ROS). Elucidating the role of HIPK2 in the regulation of iron storage proteins may provide insight into possible strategies for modulating the effects of oxidative stress.

Roles and regulation of genes encoding key proteins in iron metabolism

In his talk, Tsuji discussed the newly identified role of HIPK2 in differential phosphorylation of transcription factors, such as activating transcription factor 1 (ATF-1) and cAMP response element binding (CREB), in response to genotoxic stress. The first part of the talk was focused on gene regulation of an iron storage protein, ferritin.

According to Tsuji, ferritin H is activated in response to oxidative stress through its antioxidant response element (ARE) and is thought to have a potential role as an antioxidant in iron-catalyzed oxidative damage. ATF-1 binds ARE sites in the ferritin H enhancer region and represses gene expression.

HIPK2, as an ATF-1 binding protein, phosphorylates ATF-1 at a novel serine residue and modulates ATF-1-mediated repression of the human Ferritin H gene. Thus, HIPK2 indirectly regulates ferritin-H gene expression and imparts cytoprotection to the cells under oxidative stress.

Maintaining viability and generation of neuronal cells

The second half of the talk included Tsuji's work on the HIPK2-mediated regulation of another important transcription factor, CREB, which plays a critical role in cell survival and adaptive responses.  He further elaborated the mechanism, describing how the phosphorylation of CREB by HIPK2 at a novel site facilitates the recruitment of coactivator proteins such as CREB-binding protein (CBP) and activates the gene function.

Tsuji also showed that HIPK2 regulates the gene expression of brain-derived neurotrophic factor (BDNF) under genotoxic stress. Hence, HIPK2 has an important role in supporting neuronal cell viability and proliferation under conditions of oxidative stress.

Laboratory of Reproductive and Developmental Toxicology Chief Kenneth Korach, Ph.D., hosted Tsuji at the Receptor Mechanism Discussion Group. This monthly research seminar series provides an excellent opportunity for invited scientists to present and discuss their research work with the NIEHS scientific community.

(Ritu Rana, Ph.D., is a visiting fellow in the NIEHS Human Metabolism Group in the Laboratory of Toxicology and Pharmacology.)

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