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Clinical
Research Building, Room 437A 215-898-9072 Program or Research Summary: The EL-DEIRY LAB is a Molecular Oncology Laboratory dedicated to the
identification and characterization of cell cycle and cell death abnormalities
in chemo- and radioresistant cancers. Current areas of interest include
the identification of alterations in gene expression and regulation of
transcription by the tumor suppressors p53 and BRCA1, and by the oncoprotein
c-Myc. DNA microarrays and subtractive hybridization screens have been
yielding clues to novel pathways of cell death, cell cycle deregulation
and transformation that we are dissecting using state-of-the-art molecular
techniques. For example we have cloned the human and mouse homologues
of the TRAIL receptor DR5 (also known as KILLER) as a p53 target gene
and recently in collaboration with John Reed we identified Bax as a target
of c-Myc. In collaborative studies with Barbara Weber we identified p53
as a BRCA1 target protein, and recently we found that BRCA1 is a target
for repression by p53 in the DNA damage response. We are characterizing
several novel target genes of p53 and c-Myc. A yeast two-hybrid screen
has yielded a novel caspase-interacting protein and a novel Death Receptor
4-interacting protein that are being characterized. The isolated target
genes are being characterized through promoter analysis and the proteins
through interaction screens, and overexpression studies employing expression
plasmid, adenoviral and retroviral vectors. Our goal is to understand
the function of tumor suppressing proteins and oncoproteins through the
actions of their downstream targets. We believe such an approach is crucial
for understanding cancer pathogenesis and drug resistance and it should
also lead to novel therapeutic strategies to enhance cancer cell death
and reduce toxicity of chemo- and radiotherapy. Another area of interest
is understanding the regulation and signaling by the TRAIL family of receptors,
and the development of strategies for the use of TRAIL ligand in cancer
therapy. TRAIL is a ligand in the TNF family and is very interesting to
us because it specifically kills transformed and cancer cells but not
most normal cells. We are analyzing naturally occurring resistance to
TRAIL, as well as using genetic screens to identify cDNA's that can inhibit
cell death signaling. Detailed mutagenesis of the death domain of DR5
is suggesting strategies for modulating cell death signaling through small
moleculaes such as synthetic peptides. We are also developing strategies
for the combination of TRAIL with other agents in cancer chemotherapy
or gene therapy. The laboratory has had a long standing interest in the
p53-dependent and -independent transcriptional regulation of expression
of the p21(WAF1/CIP1) universal cell cycle inhibitor. A recent area of
interest that has emerged involves studies of the post-translational control
of the p21(WAF1/CIP1) protein. We have become interested in the cell cycle-dependent
phosphorylation of p21, the physiological relevance thereof, pathways
of transcriptional repression of p21 and the pathways of p21 degradation.
Finally, efforts are underway to understand the effects of a recently
discovered p53 mutant-conformation modifying drug. These studies which
are being performed in collaboration with scientists at Pfizer are yielding
novel insights for drug development and regulation of the p53 response. Howard Hughes Medical Institute Investigator (1995 - Present) Dr. El-Deiry authored one of the top ten most highly cited papers of the 1990's (Cell 75:817-25, 1993 "WAF1, a potential mediator of p53 tumor suppression"), and is also among the top 40 most highly cited researchers of the 1990's. (See: In-Cites) Other links of Interest: Selected Recent References: El-Deiry, W.S. Akt takes centre stage in cell-cycle deregulation. Nature Cell Biology 3:March 2001. Fisher, M.J., Virmani, A. K., Wu, L., Aplenc, J.C., Harper, J.C., Powell, S.M., Rebbeck, T.R., Sidransky, D., Gazdar, A.F., and El-Deiry, W.S. Nucleotide substitution in the ectodomain of TRAIL receptor DR4 is associated with lung cancer and head and neck cancer. Clinical Cancer Research, accepted with minor revision, 2001. Kim, K., Fisher, M.J., Xu, S.-Q., and El-Deiry, W.S. Molecular determinants of response to TRAIL in killing of normal and cancer cells. Clin. Cancer Res., 6:335-346, 2000. MacLachlan, T.K., Dash, B., Dicker, D.T., and El-Deiry, W.S. Repression of BRCA1 through a feedback loop involving p53. J. Biol. Chem., 275:31869-31875, 2000. MacLachlan, T.K., and El-Deiry, W.S. Pointing (zinc) fingers at BRCA1 targets. Nature Medicine 6:1318-1319, 2000. McDonald, E.R., III, Chui, P.C., Martelli, P.F., Dicker, D.T., and El-Deiry, W.S. Death domain mutagenesis of KILLER/DR5 reveals residues critical for apoptotic signaling. J. Biol. Chem., in press, 2001. Published On-Line 2/13/01. McDonald, E.R., III, and El-Deiry, W.S. Cell cycle control as a basis for cancer drug development. Int. J. Oncol. 16:871-886, 2000. Meng, R.D., and El-Deiry, W.S. p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-g. Exp. Cell Research, 262:154-169, 2001. Mitchell, K.O., Ricci, M.S., Miyashita, T., Reed, J.C., and El-Deiry, W.S. Identification of Bax as a transcriptional target and mediator of c-Myc-induced apoptosis. Cancer Research, 60:6318-6325, 2000. Ozoren, N. and El-Deiry, W.S. Introduction to cancer genes and growth control. In DNA Alterations in Cancer: Genetic and Epigenetic Changes. Ehrlich, M., Ed. Eaton Publishing, Natique, MA, pp. 3-43, 2000. Ozoren, N., Kim, K., Burns, T.F., Dicker, D.T., Moscioni, A.D., and El-Deiry, W.S. The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to TRAIL. Cancer Research, 60:6259-6265, 2000. Ricci, M.S., and El-Deiry, W.S. Novel strategies for therapeutic design in molecular oncology using gene expression profiles. Curr. Opin. Mol. Ther., 2:682-690, 2000. Takimoto, R. and El-Deiry, W.S. Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site. Oncogene, 19:1735-1743, 2000. Takimoto, R., and El-Deiry, W.S. DNA replication blockade impairs p53-transactivation. Proc. Natl. Acad. Sci. USA, 98:781-783, 2001. |
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