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 living cells. If not sensed and properly repaired, this damage can cause malignant transformation (cancer), in part through mutations at specific sites in certain oncogenes.
My laboratory is interesting in two different aspects of the stress response and in mechanisms that could increase the efficient of anticancer drugs. In particular we are studying 1) Chromatin modulation as a mechanism to enhance anticancer drugs efficiency, 2) Modulation of tumor suppressor functions by protein-protein interaction and 3) Role of RNA-binding proteins in the genotoxic stress response.
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 intrinsically resistant to these drugs. A Letter Of Intent (LOI) has recently been approved to extend these studies to leukemia patients. We have also shown that certain small acidic proteins can increase chromatin accessibility to enzymes that are targeted for anti cancer treatments. We are currently 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 collaboration with Dr. David Weber we are studying 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.
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 NPM inhibits p53 function by preventing its activation at lower doses of UV radiation and thus sets a threshold for p53 activation by genotoxic stress. Restoration of p53 functions by down regulation of NPM is currently under study in Ataxia Telangiectasia cells. Both, molecular biology and protein biochemistry techniques are used for these studies.
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.
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.
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.
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.
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.
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.
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).