• Associate Professor of Microbiology and Immunology
• Associate Member of the Walther Oncology Center
  
• Campus Address: R4 155
• Telephone: (317) 278-0225
• E-mail: marlsmit@iupui.edu
  

Hal Broxmeyer named distinguished professor at IUSM (click here for more details)

Janice Blum discusses Immunology & Infectious Diseases (click here for more details)

Training:
• B.Sc., 1987: University of Windsor, Canada
• Ph.D., 1992. WayneStateUniversity, Detroit, MI
• Post Doctoral, 1992-1995: University of Texas Southwestern Medical Center
• Post Doctoral, 1995-1997: HarvardUniversitySchool of Public Health

Summary of the focus of the research of Dr. Smith:
We are studying mechanisms of DNA repair that distinguish cancer cells from normal cells. The cancer-preventive agent selenium is being used to differentially regulate DNA repair levels in cancer cells versus normal cells.

Description and summary of research focus of the laboratory:
Dr. Martin Smith's laboratory has been investigating genes involved in DNA repair that are regulated by the p53 tumor suppressor. Specifically, the Gadd45a, p48XPE, and XPC proteins have been shown to be involved in the recognition of DNA damage. The p53/XPE/XPC DNA repair gene axis can be modulated by selenium in the form of selenomethione, now a subject of major clinical trials for prevention of prostate and other epithelial cancers.   Human patients or engineered mice carrying inborn gene defects in XPC or XPE exhibit defective DNA repair and are cancer-prone. Therefore the maintenance of DNA repair gene expression is likely critical to prevent carcinogenesis. In normal cells, selenium supplementation resulted in enhanced expression of XPE and XPC genes and promoted DNA repair suggesting a molecular mechanism for cancer prevention by selenium.

Importantly, normal p53 was also required to maintain DNA repair. The majority of human cancers carry nonfunctional p53 genes, suggesting that selenium might differentially affect DNA repair in normal cells versus cancer cells. Indeed, a recent study of mice bearing human xenograft tumors found that selenium protected the bone marrow and gut epithelium from chemotherapeutic toxicity (S. Cao et al, Clinical Cancer Research, 2004). Tumors remained sensitive, consistent with a role for the p53/XPE/XPC DNA repair gene axis as a molecular target of selenium differentially expressed in normal tissues and cancer cells. Clearly, selenium in the form of selenomethionine may find clinical applications beyond the current SELECT and other chemoprevention trials, and indeed may be a safe and effective means of protecting nontarget tissues and thereby greatly increasing chemotherapeutic selectivity in patients receiving chemotherapy. Dr. Smith is further defining the precise molecular targets of selenium that provide a differential response in normal cells versus cancer cells. Precise knowledge of molecular mechanisms will be key to future clinical studies.

Publications
Smith ML, Chen IT., Zhan Q, Bae I, Gilmer T, Kastan MB, O'Connor PM., and Fornace AJJr. (1994).   Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science 266:1376-1380.   

Smith ML, Chen IT, Zhan Q, O'Connor PM., and Fornace AJJr. (1995). Involvement of the p53 tumor suppressor gene in repair of UV-type DNA damage. Oncogene 10:1053-1059.

Smith ML, Ford JM, Hollander MC, Bortnick RA, Amundson SA, Seo YR, Deng C, Hanawalt PC, and Fornace AJJr. (2000). P53-mediated DNA repair responses to UV-radiation: Studies of mouse cells lacking p53, p21, and/or gadd45 genes. Molecular and Cellular Biology 20:3705-3714.

Seo YR., Fishel ML., Amundson SA, Kelley MR, and Smith ML. (2002). Implication of p53 in base-excision DNA repair: In vivo   evidence. Oncogene 21:731-737

Seo YR, Kelley MR, and Smith ML. (2002). Selenomethionine regulation of p53 by a Ref1-dependent redox mechanism. Proceedings of the National Academy of Sciences USA 99:14548-14553.

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