Research Program One:  Cell Signaling and Gene Regulation

Program Leaders:  Marsha Rosner , PhD, and Suzanne Conzen, MD

• Overview and Scientific Goals
• Program Highlights 2005-2007
   
  
  Overview and Scientific Goals
  
  
The Cell Signaling and Gene Regulation Program focuses on determining the basic cell signaling and gene expression mechanisms that underlie malignancy.  The Program has 47 members from 12 departments with a wealth of experience, which includes research in chemistry, cell signaling, systems biology, developmental biology, and drug discovery.  Research in the Program does not center on specific types of cancer; rather, it encompasses five different themes all of which focus on determining the mechanisms whereby genes, and the proteins they encode, function in both normal and cancerous conditions. Specifically, the research themes of the Cell Signaling and Gene Regulation Program are to:

1. elucidate the molecular mechanisms of tissue‑specific and cell type‑specific gene expression
2. elucidate the cellular mechanisms underlying cell growth/division and cell survival/death;
3. understand the multi‑faceted mechanisms leading to cancer metastases;
4. use large‑scale, high throughput and systems biology approaches, as well as genetic evolutionary approaches to understand cancer biology; and
5. discover novel developmental pathways relevant to cancer cell signaling.

In recent years the Program has enhanced the translational components of the program and has fostered collaborations between cancer biologists and chemists.  Both of these initiatives have been pursued in an effort to aid in the identification of potential targets and signaling pathways involved in cancer and to facilitate the testing of small molecule inhibitors of identified targets and/or pathways. 

Program Highlights 2005-2007

• Geoffrey Greene’s lab characterized the structure of a subtype‑selective estrogen receptor (ER) ligand and revealed a novel mode of ER antagonism.  This work enhances our understanding of the mechanisms of selective estrogen receptor modulator (SERM) function and provides valuable information needed for new breast cancer drug development. (Wu et al. Mol Cell 18: 413, 2005).
  
  
• Tong-Chuan (TC) He’s discovery of Wnt3A‑regulated osteogenic differentiation gene expression patterns has the potential to aid in thedevelopment of Wnt3a pathway targeted therapeutic targets for osteosarcomas.  (Si et al. Mol Cell Biol 26:2955, 2006)
  
  
• Marcus Peter and colleagues discovered a mechanism by which the non‑apoptotic function of FADD is regulated.  Understanding the differential regulation of the apoptotic and non‑apoptotic functions of FADD can aid in the development of strategies that promote the death‑inducing functions while inhibiting the proliferation‑inducing functions of this adapter protein in an effort to treat cancer(Alappat et al. Mol Cell 19:321, 2005).
  
  
• Marsha Rosner’s finding that Raf kinase inhibitory protein regulates Aurora B kinase and the spindle checkpoint (Eves et al. Mol Cell. 23:561, 2006) and her discovery, in collaboration with Dr. Ezra Cohen (Clinical and Experimental Therapeutics Program), that PKC-ζ mediates epidermal growth factor‑induced growth of head and neck tumor cells by regulating MAP kinase have led to further studies (in progress and proposed) of the use of specific kinase inhibitors as cancer therapies.
  
  
• Wei Du and colleagues discovered that the loss of cyclin D1 impairs cerebellar development and suppresses medulloblastoma formation (Pogoriler et al. Development 133:3929, 2006).  This study suggests that cyclin D1 may be a useful target of inhibition when designing drugs for the treatment of central nervous system tumors.
  
  
• Tong-Chuan (T. C.) He’s lab, in collaboration with clinician scientists Drs. Luu and Peabody (Clinical and Experimental Therapeutics Program), developed of a novel orthotopic model of human osteosarcoma growth and spontaneous pulmonary metastasis (Luu et al. Clin Exp Metastasis 22:319, 2005).  This model should be a useful tool for thepre‑clinical screening of therapeutic compounds to prevent the development of metastatic osteosarcoma.
  
  
• The National Human Genome Research Institute, part of the National Institutes of Health, has awarded $9.1 million over four years to a research team led by Kevin White, PhD and the University of Chicago (to includeresearchers from the University of California San Diego, Massachusetts Institute of Technology, Baylor College of Medicine and Cambridge University) to identify all regulatory elements in the fruit fly genome as part of the ENCyclopedia of DNA Elements (ENCODE) project.

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Program 1
Cell Signaling and Gene Regulation
Program Leaders: Marsha Rosner, PhD and Suzanne Conzen, MD

Program 2
Molecular Genetics and Hematopoiesis
Program Leaders: Wendy Stock, MD and Michael Thirman, MD

Program 3
Immunology and Cancer
Program Leader: Thomas F. Gajewski, MD, PhD

Program 4
Clinical and Experimental Therapeutics
Program Leaders: Everett E. Vokes, MD and M. Eileen Dolan, PhD

Program 5
Advanced Imaging
Program Leaders: Maryellen L. Giger, PhD and Heber MacMahon, MD

Program 6
Cancer Risk and Prevention
Program Leaders: Olufunmilayo (Funmi) I. Olopade, MBBS and Andrea King, PhD