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SIGNAL TRANSDUCTION IN CANCER: dissecting the molecular mechanisms by which normal cells become cancerous and metastasize
Our laboratory is located in the Biomedical Research Building II/III at the University of Pennsylvania School of Medicine.
Our main research interest is in the area of SIGNAL TRANSDUCTION IN CARCINOGENESIS. Our laboratory investigates the intracellular pathways that contribute to malignant transformation and metastatic dissemination of cancer cells in various models, including breast, prostate, and lung cancer. One of our major goals is to elucidate the role of the lipid second messenger diacylglycerol (DAG) as a modulator of proliferation, survival, apoptosis, differentiation, and transformation. DAG is generated mainly by the action of phospholipase C (PLC) isozymes in response to the activation of tyrosine kinase receptors and G protein-coupled receptors (GPCRs), and it activates several families of intracellular targets, one of which is the protein kinase C (PKC) family. Phorbol esters, a class of tumor promoters, mimic the action of DAG, as they bind to the C1 domain, a 50-51 amino acid domain present in the regulatory region of PKC isozymes. We have established key roles for PKC isozymes in cell cycle progression, apoptosis, senescence, and metastasis, and set mechanistic bases for targeting these kinases for cancer treatment.
In recent years, the traditional view of PKCs as the sole receptors for phorbol esters has been challenged with the discovery of proteins unrelated to PKC that bind DAG and phorbol esters with high affinity, suggesting a high degree of complexity in the signaling pathways activated by DAG. These molecules include chimaerins, Munc13s, RasGRPs and DAG kinases. A main goal in our laboratory is to understand how this "non-PKC" DAG/phorbol ester receptors" modulate pathways relevant to tumorigenesis. Our laboratory has characterized the "chimaerins", a family of Rac-GAPs, and found that they are downstream effectors of receptors, such as the EGF receptor. Chimaerins inhibit the activity of Rac, as small G-protein that controls actin cytoskeleton reorganization, mitogenesis, migration and metastatic dissemination. We have established fundamental roles for chimaerins negatively modulate all these cellular events and we are currently assessing their potential roles as tumor suppressors. In addition, we are investigating the involvement of Rac and their activators (the Rac-GEF exchange factors) as downstream effectors and mediators of ErbB receptors, such as the EGF receptor, ErbB2, and ErbB3.
Our challenge is to elucidate such complex signaling mechanism with the ultimate goal of finding novel targeting molecules for cancer therapeutics using cellular, genetic and pharmacological approaches. These are the major areas currently under investigation:
- PKC and prostate carcinogenesis: from the genes to animal models.
- PKC as a modulator of the cell cycle in lung cancer.
- Chimaerins: DAG/phorbol esters with Rac-GAP activity.
- Involvement of Rac-GAPs and Rac-GEFs and in ErbB receptor signaling
I hope that this web page gives you a flavor of our research interests. Feel free to contact us.
Marcelo G. Kazanietz, Ph.D.
Professor of Pharmacology
University of Pennsylvania School of Medicine
1256 Biomedical Research Building II/III
421 Curie Blvd., Philadelphia, PA 19104-6160