Reza Zarnegar, PhD
- Professor of Pathology
200 Lothrop Street
Department of Pathology
Pittsburgh, PA 15261
200 Lothrop Street
Department of Pathology
Pittsburgh PA 15261
About the Principal Investigator:
Dr. Zarnegar is a Tenured Professor of Pathology and a member of the Division of Experimental Pathology. His laboratory is focused on determining the physiological and pathological role of the HGF/Met axis in normal tissue homeostasis and disease processes.
Dr. Zarnegar discovered Hepatocyte Growth Factor (HGF) in the 1980's when he was a Research Assistant Professor at Duke University. Since then, he has devoted his research efforts on understanding this important signaling factor. HGF and its cell surface tyrosine kinase receptor (Met) play an important role in tissue homeostasis, and the deregulation of HGF/Met axis has pathological consequences such as cancer. An in-depth understanding of the molecular mechanisms of HGF/Met function will not only shed light on normal tissue physiology but also on understanding the bases of its pathogenic effects and thus may provide opportunities for rational drug design to combat various diseases ranging from tissue degeneration to cancer.
Through structural and functional studies, Dr. Zarnegar's laboratory has discovered novel mechanisms by which the Met receptor regulates hepatocyte growth and liver homeostasis. Specifically, his lab found that, in normal liver, the extracellular domain (a.k.a. the ectodomain) of Met directly binds to Fas (a death promoting receptor) and acts as a natural antagonist of FasL thereby prohibiting Fas aggregation and cell killing. They have determined that Fas sequestration by Met is abrogated in human fatty liver disease hence making these livers vulnerable to cell death and development of NASH. The mechanism through which liver cells die is mainly via activation of the Fas axis. Unregulated hepatocyte death occurs in a variety of hepatic diseases including hepatitis caused by chemical, viral or metabolic etiologies which may ultimately culminate in end-stage liver disease including liver cancer and hepatic failure requiring liver transplantation. Dr. Zarnegar's group has mapped the interaction region in Met and Fas to a 12 amino acid region containing a core YLGA motif in Met and show that Met and its synthetic peptide derivatives prohibit FasL binding to Fas, Fas activation and hepatocyte death in vitro and in animal models of NASH (Figure 1). His lab is currently expanding these structure-function studies of Met.
In a separate project, Dr. Zarnegar's lab has discovered that, in human breast cancer, the HGF gene promoter is prone to deletion mutagenesis in a DNA element located 750 bp upstream from the transcription start site. This novel HGF promoter element consists of a mononucleotide repeat of 30As and is referred to as DATE (Deoxy Adenosine Tract Element). Mutation of DATE results in reactivation/lack of proper silencing of HGF gene expression in carcinoma tissues. Normally, the HGF gene is transcriptionally silenced in differentiated breast epithelial cells. Through functional studies, they showed that DATE mutation (shortening) has profound local and global effects on the HGF promoter region by modulating chromatin structure and DNA-protein interactions leading to constitutive activation of the HGF gene promoter in human breast carcinoma cells lines. Interestingly, they found that 51% (19/37) of African Americans and 15% (8/53) of Caucasians with breast cancer harbor the truncated DATE variant (25As or less) in their breast tumors and that the truncated allele significantly associates with cancer incidence and aberrant HGF expression (Figure 2).
Carla Johnson, B.S.
Current Lab Members:
Dr. Jihong Ma, Research Associate
Dr. Chunbin Zou, Research Associate
RELEVANT RECENT PUBLICATIONS:
View Dr. Zarnegar's publications on PubMed
- Wang, X. DeFrances, M.C., Dai, Y. Bell, A., Michalopoulos G.K. and Zarnegar, R. (2002). A novel mechanism of cell survival: sequestration of the death receptor Fas by direct physical association with the tyrosine kinase receptor Met. Molecular Cell 9: 411-422. [Subject of a commentary entitled "A dual purpose anti-death agent" in the Research Roundup section of the Journal of Cell Biology, Volume 156:941, 2002].
- Zou, C., Ma, J., Wang, X, Guo, L., Zhu, Z., Stoops, J., Eaker, A.E., Johnson, C., Strom, S., Michalopoulos, G.K., DeFrances, M.C., and Zarnegar, R. Lack of Fas antagonism by Met in human fatty liver disease: The alpha chain of Met is a natural antagonist of FasL via a novel YLGA motif (2007). Nature Medicine. 13 (9): 1078-1085. [Subject of commentaries by Christian Trautwein and Daniela Kroy (2008) entitled "Peptide-Based NASH Therapy, A First Crucial Step Soon Clinical Reality?" Hepatology 47: 757-758] and by Susanne Strand and Peter R. Galle. entitled "Getting the Fat out of Met and Fas". J. of Hepatology, 49: 479-482 (2008)].
- Ma, Jihong, Marie C. DeFrances, Chunbin Zou, Carla Johnson, Robert Ferrell, and Reza Zarnegar. Somatic Mutation and Functional Polymorphism of a Novel Regulatory Element in the HGF Gene Promoter Causes Its Aberrant Expression in Human Breast Cancer (2009). Journal of Clinical Investigations. 119 (3) March issue (Note: available on-line In February 2009 via the JCI site.)