Sabrina E. Brzostek
B.S. Boston College, 2000

7th Year Graduate Student

Advisor: Nancy Reich, Ph.D.

Department: Molecular Genetics & Microbiology

Graduate Program: Molecular Genetics & Microbiology

Abstract:

Title:  Effect of Etoposide on Interferon Signaling 

A cellular DNA damage response is activated during the course of infection by a number of viruses. Viruses, such as Herpes Simplex Virus, Adenovirus and Human Papilloma Virus, have evolved strategies to inhibit the molecular and cellular effect of DNA damage that can result in apoptosis. To better understand the cellular response to DNA damage, we evaluated the effects of DNA damaging agents, such as etoposide, on gene expression. Etoposide, a chemotherapeutic drug used to treat various cancers, causes cell cycle arrest and death by apoptosis. Its mechanism of action involves the targeting of topoisomerase II, resulting in an increase the number of double stranded breaks in the DNA. Ultimately, this damage triggers cell death pathways, leading to apoptosis. We compared the gene expression profile of etoposide treated cells to that of virally infected cells. Our studies indicate that etoposide treatment leads to expression of interferon (IFN) stimulated genes (ISGs). Further analysis indicates that a subset of IFNα and IFNλ genes are induced by the DNA damage incurred with etoposide treatment and the ISGs are expressed as a result of IFN signaling. The activation pathways that lead to IFNα and IFNλ induction are currently being investigated. The IFN Regulatory Factors (IRFs), IRF3, IRF5 and IRF7 do not appear to be activated and thus are not responsible for this IFN gene induction. However, the NFkB family of transcription factors is activated in response to etoposide and appears to signal the induction of this subset of IFN genes.

These studies begin to make a significant link between two host survival mechanisms, the cellular response to DNA damage and the protective effects of IFN signaling.

Publications:
(MSTP-supported publications indicated with an *)

Cohen RN, Brzostek S, Kim B, Chorev M, Wondisford FE, Hollenberg AN. (2001). The specificity of interactions between nuclear hormone receptors and corepressors is mediated by distinct amino acid sequences within the interacting domains. Mol Endocrinol. Jul;15(7):1049-61.

Cheng S, Brzostek S, Lee SR, Hollenberg AN, Balk SP. (2002). Inhibition of the dihydrotestosterone-activated androgen receptor by nuclear receptor corepressor. Mol Endocrinol. Jul;16(7):1492-501.

Makowski A, Brzostek S, Cohen RN, Hollenberg AN. (2003). Determination of nuclear receptor corepressor interactions with the thyroid hormone receptor. Mol Endocrinol. Feb;17(2):273-86.

*Cheng TF, Brzostek S, Ando O, Van Scoy S, Kumar KP, Reich NC. (2006). Differential Activation of IFN Regulatory Factor (IRF)-3 and IRF-5 Transcription. J Immunol. 176: 7462-7470.