Mark I. Greene, M.D., Ph.D., F.R.C.P.
John Eckman Professor of Medical Science, Dept of Pathology

Cancer Biology Program

Address

252 John Morgan Building
3620 Hamilton Walk
Philadelphia, PA 19104

Office tel.: 215 898-2847
Lab tel.: 215 898-2870
Fax: 215 898-2401
E-mail: greene@reo.med.upenn.edu


EDUCATION

University of Manitoba: 1966-1968.

University of Manitoba: MD, 1972.

Fellow of the Royal College of Physicians: F.R.C.P., (Internal Medicine), 1976.

University of Manitoba: PhD (Immunology), 1977.

RESEARCH INTERESTS

• Receptor function, small molecules, centrosome and associated proteins.

Key words: Receptors, cancer, structure.

Search PubMed for articles

DESCRIPTION OF RESEARCH

Dr. Greene's research is concerned with defining the principles of receptor function. An area he has concentrated on for the last 19 years involves members of the erbB gene family. Greene's laboratory discovered that pl85c-neu could associate with EGFR to form a heteromeric assembly. This heteromeric complex possessed unique properties including increased kinase activity. The heterodimers had a higher affinity for EGF than homomeric forms of the EGFR receptor and were found to represent the major signaling receptor form. Heteromer formation was found to be preferred over homomeric assembly and the ectodomains were found essential in stabilizing the dimeric species.

Greene's laboratory developed an approach to target and down-modulate oncoproteins which when expressed were critical for abnormal growth. This simple approach developed in the neu system involved developing monoclonal antibodies specific for the ectodomain of pl85. The approach was to take advantage of the formation of kinase active homomeric (pl85-pl85) or heteromeric (pl85c-neu-EGFr) assemblies found on malignant cells and which were active in mediating the transformed phenotype. Normal receptor species which are not activated are in a kinase inactive configuration. Furthermore, down modulation of normal receptors is not associated with cell injury. This was the basis for targeted therapy and the approach has led to an improved treatment for advanced breast cancer.

Greene has recently begun to design organic molecules that disable protein function. His laboratory uses crystallography and thermodynamic analyses to help define cavities near active sites that are used to lodge organic molecules. These cavity filling molecules induce allosteric changes in the active sites leading to modification of protein function.

As part of the studies to define the progression of the transformed phenotype, Greene's laboratory has focused on the assembly and function of the mammalian centrosome. His group has identified several new genes that encode centrosomal proteins that appear relevant to the centrosome assembly pathway. Certain of these genes are also relevant to the spindle checkpoint.

Berezov, A., Chen, J., Liu, Q., Zhang, H., Murali, R., and Greene, M.I. Disabling Receptor Ensembles with Rationally Designed Interface Peptidomimetics, The Journal of Biological Chemistry, 277:28330-28339, 2002.

Kumagai, T., Katsumata, M., Hasegawa, A., Funakoshi, T., Kawase, I., and Greene, M.I. Role of extracellular subdomains of p185c-neu and the epidermal growth factor receptor (EGFR) in ligand-independent association and ligand-induced transactivation. Proc. Natl. Acad. Sci., 100: 9220-9225, 2003.

Zhang, H.T., Richter, M., and Greene, M.I. Therapeutic monoclonal antibodies for the erbB family of receptor tyrosine kinases. Cancer Biology and Therapy 1, 90-96, 2003.

Hasegawa, A., Cheng, X., Kajino, K., Berezov, A., Murata, K., Nakayama, T., Yagita, H., Murali,R., and Greene, M. I. Fas Disabling Small Exocyclic Peptide Mimetics Limit Apoptosis by an Unexpected Mechanism. Proc. Natl. Acad. Sci., 101:6599-6604, 2004.

Wang, Q., Furuuchi, K., Hirohashi, Y., Zhao, H., Liu, Q., Zhang, H., Murali, R., Berezov, A., Du, X., Li, B., and Greene, M. I. The Centrosome in Normal and Transformed Cells. DNA and Cell Biology, 23 (8):475-489, 2004.

Lab

ROTATION PROJECTS FOR 2006-2007

Please contact Dr. Greene for possible laboratory rotations.

Lab personnel:

Mark I. Greene, M.D., Ph.D., F.R.C.P. (Professor)
Alan Berezov, Ph.D. (Research Associate)
Xin Cheng, Ph.D. (Research Associate)
Xiulian Du, Ph.D. (Postdoctoral Researcher)
Keiji Furuuchi, Ph.D. (Postdoctoral Researcher)
Narumi Furuuchi, (Research Specialist)
Makoto Katsumata, Ph.D. (Research Specialist)
Bin Li, Ph.D. (Postdoctoral Researcher)
Qingdu Liu, Ph.D. (Postdoctoral Researcher)
Gail Massey, Ph.D. (Research Specialist)
Mayosha Mendis, (Research Specialist)
Ramachandran Murali, Ph.D. (Research Assistant Professor)
Sandra Saouaf, Ph.D. (Research Specialist)
Qiang Wang. Ph.D. (Research Associate)
Jennifer Wolfe (Administrative Assistant)
Hong Tao Zhang, Ph.D. (Research Specialist)
Huiwu Zhao, Ph.D. (Postdoctoral Researcher)