France Carrier, Ph.D. Assistant Professor      108 N. Greene St.      Baltimore, MD 21201      Phone: 410-706-5105      Fax: 410-706-8297      email: fcarr001@umaryland.edu EDUCATION 1983   B.Sc., Medical Biology, University of Quebec at Trois-Rivières           Québec, Canada 1986   M.Sc. Clinical Sciences/Biochemistry, University of Montreal,           Québec, Canada 1988   Ph.D., Clinical Sciences/Biochemistry, University of Montreal           Québec, Canada POST GRADUATE EDUCATION 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.

PROFESSIONAL EXPERIENCE

The capacity to constantly monitor the damage inflicted to one’s genetic material (genotoxic stress) is one of the most critical mechanisms regulating the homeostasis of lived cells.  Free radicals and peroxides, generated during normal physiological processes and inflammation, as well as environmental pollutants, ultra-violet light, and ionizing radiation are the most common sources of DNA damaging agents.  If not sensed and properly repaired, this damage can cause malignant transformation (cancer), in part through mutations at specific sites in certain oncogenes.  In normal human cells, the genotoxic stress response is rather complex.  It includes the induction of several genes that have been associated with a number of important cellular events such as cell cycle control, signal transduction, replication, mutagenesis, transcription, DNA repair and viral activation.  In general, stress activated genes and proteins play a protective role to prevent the transmission of damaged DNA to the next generation of cells. 

My laboratory is interested in two particular aspects of the cellular response to genotoxic (DNA damage) stress in human cells.  1) We are studying the role of stress-activated RNA-binding proteins (RBP) in the genotoxic stress response and 2) We are studying the interactions of stress-activated proteins with chromatin DNA as a potential mechanism to increase the efficiency of anticancer drugs.  1) We have identified three stress-activated RBP proteins, A18 hnRNP, nucleolin and nucleophosmin (NPM).  These proteins play important roles in translation, replication and repair.  Of particular interest is the interaction of NPM with the tumor suppressor p53.  p53 is the most mutated gene is human cancer, it is estimated that more than 50% of human tumors have a mutation in that gene.  Our data indicate that levels of NPM can set a threshold for p53 activation in response to DNA damaging agents.  This effect is currently explored to restore p53 activity in Ataxia Telangiectasia cells. 2) We have recently demonstrated that brief opening of the chromatin structure by histone deacetylase inhibitors, prior to treatment with anticancer drugs that target DNA, increases the anti cancer drugs efficiency by more than ten fold in cell lines that are clinically resistant to these drugs.  This set the stage for the development of a new clinical trial for relapsed and/or acute leukemia and myelodysplastic syndromes. We have also shown that certain small acidic proteins can increase chromatin accessibility to enzymes that are targeted for anti cancer treatments.  We are exploring the capacity of these proteins to open up the chromatin structure to enhance anticancer drugs’ efficiency in tumor cell lines that are resistant to the drugs. 

In addition, we are actively pursuing a third project in collaboration with Dr. David Weber where we study the interaction of the tumor suppressor p53 with the S100 calcium binding proteins.  Drugs that can potentially disrupt the p53-S100 interaction are currently under study.

SELECTED PUBLICATIONS
Kim, M.S., Baek, J.H., Chakravarty, D., Sidransky, D. and Carrier, F^#.  Sensitization to UV-induced apoptosis by the histone deacetylase inhibitor Tricostatine A.  Experimental Cell Research, 306, 94-102, 2005.

Cha, H., Hancock, C., Dangi, S., Maiguel, D., Carrier, F., and Shapiro, P.  Phosphorylation regulates nucleophosmin targeting to the centrosome during mitosis as detected by cross reactive phosphorylation specific MKK1/2 antibodies.  Biochem.J, 378, 857-865, 2004.

Maiguel, D.A., Jones, L., Chakravarty, D., Yang, C., and Carrier, F^#.  Nucleophosmin sets a threshold for p53 response to UV radiation. Molecular and Cellular Biology, 24, 9, 3703-3711, 2004. 

Lin, J., Yang, Q., Yan, Z., Markowitz, J.M., Wilder, P., Carrier, F^# and Weber, D.J.  Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells. J.Biol.Chem. August 6: 279 (32), 34071-34077, 2004.

Markowitz, J., Chen, I., Gitti, R., Baldisseri, D.M., Pan, Y., Udan, R., Carrier, F., MacKerell, A.D., Jr., Weber, D.J.  Identification and characterization of small molecule inhibitors of the calcium-dependent S100B-p53 tumor suppressor interaction.  J. Med. Chem., 47, 5085-5093, 2004.