• 1983 - B.Sc., Medical Biology, University of Quebec at Trois-Rivieres Quebec, Canada
• 1986 - M.Sc. Clinical Sciences/Biochemistry, University of Montreal, Quebec, Canada
• 1988 - Ph.D., Clinical Sciences/Biochemistry, University of Montreal Quebec, Canada

• 1988-1989 - Postdoctoral fellow, Protein Engineering group, Biotechnology Research Institute, National Research Council, Montreal Canada.
• 1989-1991 - Guest Researcher, Developmental Pharmacology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
• 1991-1998 - Visiting Associate, Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

• 1992-present: American Association for Cancer Research
• 1992-2003: American Association for the Advancement of Science
• 2000-present: New York Academy of Sciences
• 1999-present: Cosmos Club, Washington, D.C.

• 1988: International fellowship. Visiting fellowship from the National Research Council of Canada
• 1989: Canadian fellowship. Postdoctoral fellowship from "Fonds de la Recherche en Santo du Quebec"
• 1990: International fellowship. Among the first awardees of a Long-term postdoctoral fellowship from the Human Frontier Science Program Organization.
• 1991: International fellowship. Visiting associate Fellowship from the National Institutes of Health
• 1994: Co-author on the second most-cited paper in biology in 1994. Science Watch, September 1994, p.5; Kastan, M., B., Zan, Q., El-Deiry, W., S., Carrier, F., Jacks, T., Walsh, W., V., Plunkett, B., S.,Vogelstein, B., Fornace, A.J.,Jr. A Mammalian cell cycle checkpoint pathway utilizing p53 and GADD 45 is defective in Ataxia Telangiectasia. Cell 71: 587-597, 1992
• 1995: Federal Technology Transfer Award from the National Institutes of Health, National Cancer Institute
• 1996: Certificate of appreciation for being a mentor in the student and teacher internship program (1995-1996) from the Howard Hughes Medical Institute, Montgomery County Public Schools and the National Institutes of Health
• 1998, 1999: Intramural award entitled: "Induction of Mammalian RNA-Binding Proteins" from the office of the Dean, University of Maryland, School of Medicine
• 2001: Graduate Student Research Day Award, 2nd Place in Molecular Biology (Dony Maiguel)
• 2002: Brigid Leventhal Award from the American Association for Cancer Research (Myoung Sook Kim). Inhibition of histone deacetylase increases Topoisomerase Inhibitors efficiency in cells clinically resistant to Top2 inhibitors. Myoung Sook Kim, Mellissa Blake, Jin Baek and France Carrier
• 2002: Graduate Student Research Day Award, 2nd Place in Molecular Biology (Dony Maiguel)
• 2003: Graduate Student Research Day Award, 1st Place in Molecular Biology (Jing Lin)
• 2003: Graduate Student Research Day Award, 2nd Place in Molecular Biology (Dony Maiguel)
• 2004-2007: Biography selected for publication in Who's Who in America
• 2004-2007: Biography selected for publication in Who's Who in the World
• 2004-2007: National Kidney Foundation. Post-doctoral fellowship (Devulapalli Chakravarty)
• 2004: Consultant for "Defined Health" on Colorectal Cancer

My laboratory is interested in understanding molecular events underlying cancer progression. Our goal is to delineate intrinsic differences between normal and cancer cells in order to more specifically target cancer cells and improve current cancer therapies.

Carcinogenesis is a multiple steps process that includes, initiation, promotion, transformation and finally propagation of the cancer cells. My main interest focuses on the first two steps of carcinogenesis, initiation and propagation and most recently we have been involved in cancer treatments, which target the last step of carcinogenesis, propagation. The initiation step is usually triggered by exposure to carcinogens that can damage DNA. The cellular response that ensues, genotoxic stress response, is complex but generally plays a protective role against the cellular insults. Our studies on the genotoxic stress response have focused on the role of stress-activated RNA binding proteins. We are mainly interested on the role of hnRNP A18, nucleolin (NCL) and nucleophosmin (NPM), three stress-activated proteins, in responses to cellular insults. We have shown that hnRNP A18 can increase cell survival in response to DNA damaging agents by stabilizing the transcripts of genes known to play a protective role against cellular insults (1). Activation of hnRNP A18 is mediated by the hypoxia inducible GSK-3B protein kinase (2). We have identified a consensus hnRNP A18 binding motif in several mRNAs transcripts including the ATM and Rad3 related kinase ATR. ATR is a member of the PI3K kinases and is important for cellular replication under normal and stressed conditions. Its regulation is largely unknown. Our goal for this project is to determine whether GSK-3B regulates hnRNP A18 RNA binding activity similarly in normal and cancer cells and whether it can affect replication through ATR regulation. In the long-term, we would also like to understand the structural changes that lead to hnRNP A18 increased RNA binding activity upon phosphorylation. The structural information could lead to the development of new chemotherapeutic drugs that could specifically modify hnRNP A18 RNA binding activity.

Both, Nucleolin (NCL) and Nucleophosmin (NPM) have nucleotide and protein-protein binding activities. The over-expression of NCL and NPM in several cancer cell lines compared to normal cells prompted us to investigate their involvement in cancer progression. Our model is the cancer prone syndrome Ataxia Telangiectasia (AT). We and others (3, 4) have shown that over expression of NPM or NCL prevent p53 activation in colorectal and breast cancer cell lines. Here we hypothesize that these two proteins could also prevent the activation of the wild type p53 protein in AT cells. Our most recent data indicate that down regulation of either NPM or NCL increase AT cells survival in response to the xr-mimetic agent bleomycin. In addition, expressing wild type ATM kinase in ATM deficient fibroblast leads to down regulation of NCL and NPM phosphorylated at Ser125. This result suggested that in normal cells, a functional ATM activates a phosphatase that prevents phosphorylation of NPM at Ser125 and possibly the over-expression of NCL. We verified this possibility by down regulating the protein phosphastase 1 (PP1) in cells expressing wild type ATM. This indeed led to up-regulation of NCL and NPM phosphorylated at Ser125. Our long-term goal is to identify drugs or peptides that could restore p53 activity by reducing its interaction with NPM and/or NCL.

Propagation is the last and most devastating step of carcinogenesis. A major goal of several chemotherapeutic regimens is therefore to prevent or inhibit this step. The inhibitors of histone deacetylases (HDACIs) are considered one of the most promising anticancer drugs in development (5). As their name suggests, their primary targets are enzymes that deacetylate histones but several non-histone targets have also been described. HDACIs are effective as single or combination agent against cancer cell proliferation. They are about ten times more efficient on cancer cells as compared to normal cells. The reason for this preferred sensitivity is not known. We have shown(6,7)that pre-treatment of cancer cells with HDACIs sensitize cancer cells to conventional chemotherapeutic agents. As part of a team lead by Dr. Douglas Ross at the University of Maryland Greenebaum Cancer Center, we are currently investigating the effect of HDACI pretreatment in a Phase 1 clinical trial for relapsed and/or refractory acute leukemias and myelodysplastic syndromes. We are also investigating the possibility that intrinsic chromatin differences are responsible for the increased sensitivity of cancer cells to HDACIs.

References

1. Yang, C. and Carrier, F. The UV-inducible RNA-binding protein A18 (A18 hnRNP) plays a protective role in the genotoxic stress response. J Biol Chem, 276: 47277-47284, 2001.

2. Yang, R., Weber, D. J., and Carrier, F. Post-transcriptional regulation of thioredoxin by the stress inducible heterogenous ribonucleoprotein A18. Nucleic Acids Res, 34: 1224-1236, 2006.

3. Maiguel, D. A., Jones, L., Chakravarty, D., Yang, C., and Carrier, F. Nucleophosmin sets a threshold for p53 response to UV radiation. Mol Cell Biol, 24: 3703-3711, 2004.

4. Takagi, M., Absalon, M. J., McLure, K. G., and Kastan, M. B. Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin. Cell, 123: 49-63, 2005.

5. Minucci, S. and Pelicci, P. G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer, 6: 38-51, 2006.

6. Kim, M. S., Blake, M., Baek, J. H., Kohlhagen, G., Pommier, Y., and Carrier, F. Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res, 63: 7291-7300, 2003.

7. Carrier, F. Blake, M., Khelifa, T. Chromatin structure opening by the Histone Deacetylase Inhibitor Trichostatin A (TSA) increases cellular cytotoxicity to Topoisomerase inhibitors. In: American Association for Cancer Research, New Orleans, LA, March 2001, pp. #1354.

In addition to the work described above we are also involved in collaborative projects and/or funded grants focused on: the interaction of the S100B protein with p53 (Dr. David Weber, U of Md, Alex Mackerell, School of Pharmacy, U of Md), Translational Trial of SAHA in combination with Arabinosyl Cytosine and Etoposide for Patients with Relapsed and/or refractory acute Leukemias and Myelodysplastic Syndromes (Dr. Douglas Ross, Marlene and Stewart Greenebaum Cancer Center U of Md), the role of Nucleophosmin in centrosome duplication (Paul Shapiro, School of Pharmacy), the role of the Purkinje cell-2 protein in the Ataxia Telangiectasia neurodegeneration (Dr. Yuan Luo, School of Pharmacy), effect of simulated space radiation on chromatin structure and gene expression (Elizabeth Balcer-Kubiczek, Radiation Oncology, U of Md).

Translational Research

Cell and Molecular Biology Techniques