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M. Celeste
Simon, Ph.D.
Professor, Department of Cell and Developmental Biology
Investigator, Howard Hughes Medical Institute
Abramson Family Cancer Research Institute
University of Pennsylvania Cancer Center
Cancer Biology Program
Address
456 BRB II/III (Office)
438 BRB II/III (Lab)
421 Curie Boulevard
Philadelphia, PA 19104-6160
Office tel.: (215) 746-5532
Lab tel.: (215) 746-5526
Fax: (215) 746-5511
E-mail: celeste2@mail.med.upenn.edu
Link(s)
M.
Celeste Simon at the Abramson Institute
Education
Miami University, B.A. (Microbiology), 1977
Ohio State University, M.S. (Microbiology), 1980
The Rockefeller University, Ph.D. ( Molecular Biology), 1985
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Research
Interests
- Our laboratory studies stem cells, hematopoiesis, angiogenesis,
tumorigenesis, and cellular responses to oxygen deprivation.
Key
words: stem cells, angiogenesis, hematopoiesis,
cancer, hypoxia, tumor suppressors, mouse models of human
malignancy.
Description
of Research
Our laboratory has conclusively shown that a
protein complex called hypoxia inducible factor (HIF) regulates
how cells adapt to oxygen (O2) deprivation. Furthermore,
by deriving HIF mutant ES cells and mice, we have established
that HIF is essential for blood cell, blood vessel, placental,
and cardiac development during embryogenesis. Because a solid
tumor cannot grow unless it acquires new blood vessels from
surrounding host tissues, HIF is also necessary for tumor
progression. Mutations in at least four genes known to suppress
tumor growth lead to HIF stimulation and tumor growth and
angiogenesis. By identifying the molecules that require HIF's
ability to promote blood vessel growth and tumor cell survival,
we hope to develop a procedure that will cut off the tumor's
O2 supply and diminish the cancer cell's ability
to metastasize
The division, differentiation, and function of stem cells and multipotent progenitors are influenced by complex signals in the microenvironment, including O2 availability. We have shown that two factors, HIF-1a and HIF-2a directly regulate stem cell maintenance and differentiation. We are currently deleting HIF-1α and HIF-2α in mouse strains that develop tumors in the lung, liver, and kidney to genetically dissect their roles in tumor progression (i.e. latency, size, vascularity, and metastasis). We are also evaluating a role for HIF-1α and HIF-2α in both normal and cancer stem cell maintenance.
Progress has been made in understanding the transcriptional mechanisms activated during hypoxia, but the underlying mechanisms of O2 sensing by mammalian cells are not completely understood. We have shown that hypoxia activates HIF via a mitochondrial-dependent signaling process involving increased reactive oxygen species. Therefore, we believe that mitochondria act as O2 sensors by increasing the generation of reactive oxygen species during hypoxia. We are currently studying how this directly affects HIF stabilization and activity. We are also studying how HIF and its targets, like vascular endothelial growth factor (VEGF) are preferentially translated while most mRNAs are not in hypoxic cells (to conserve ATP). This will allow the identification of mRNAs selectively translated in cells experiencing the metabolic stress of O2 deprivation.
Research Techniques:
Generation of standard and conditional knock out and transgenic mice, mouse models of human cancer, ES cell technology, stem cell biology, embryology, ex vivo developmental models of organogenesis, in vivo models of neoplasia, gene expression profiling utilizing Affymetrix microarrays, array cGH, molecular biology, biochemistry, histology, immunohistochemistry, in situ hybridization, animal surgery, electron microscopy, confocal microscopy, and cell imaging.
Selected
Publications
Gordan, J. D., J. A. Bertout, C.-J. Hu, J. A.
Diehl, and M. C. Simon (2007) HIF-2 promotes hypoxic cell
proliferation by enhancing c-Myc transcriptional activity.
Cancer Cell 11:335-347.
Keith, B. and M. C. Simon (2007) Hypoxia inducible
factors, stem cells, and cancer. Cell 129:465-472.
Hickey, M. M., W. K. Rathmell, J. C. Lam, N.
A. Bezman, and M. C. Simon (2007) von Hippel-Lindau mutation
in mice recapitulates Chuvash polycythemia via hypoxia-inducible
factor-2 signaling and splenic erythropoiesis. J. Clin.
Invest. 117:3879-3889.
Simon, M. C. and B. Keith (2008) The role of
oxygen availability in embryonic development and stem cell
function. Nature Reviews Mol. Cell Biol. 9:285-296.
Bertout, J. A., J. D. Gordan, D. Ditsworth,
E. J. Brown, K. L. Nathanson, and M. C. Simon (2008) HIF2
enhances tumor cell radioresistance by limiting DNA damage
and binding the p53-MDM2 complex to promote p53 degradation.
Mol. Cell, manuscript submitted. 
Search PubMed for more articles
Lab
Rotation
Projects:
Continued analysis of the role of hypoxia-inducible factors and tumor suppressors in stem cell function, angiogenesis, hematopoiesis, and tumor progression. Other projects will focus on cellular oxygen sensing and distinct adaptations provided by HIF-1 versus HIF-2.
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Lab Personnel:
Jessica Bertout, Vet. Ph.D. Student
Tim Cash, Ph.D. Student
Vijay Dondeti, Ph.D. Student
Brian Keith, Adjunct Associate Professor
Jennifer Lam, Research Technician
Amar Majmundar, M.D., Ph.D. Student
Lijoy Mathews, Postdoctoral Fellow
Jolly Mazumdar, HHMI Associate (Postdoctoral Fellow)
Guoliang Qing, HHMI Associate (Postdoctoral Fellow)
Shetal Patel, M.D., Ph.D. Student
Theresa Richardson, Research Specialist
Davesh Shah, Undergraduate Research Assistant
Nicolas Skuli, HHMI Associate (Postdoctoral Fellow)
Waihay Wong, M.D. Ph.D. Student
Gina Young, Research Associate (Postdoctoral Fellow)
Hongwei Yu, Research Specialist
Hongxia Zhang, HHMI Associate (Postdoctoral Fellow)
last updated 7/2008
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