Research / Clinical Summary

Dong-Er Zhang, PhD Professor, Molecular and Experimental Medicine Tumor Growth, Invasion & Metastasis Program Contact by Email Visit the Website

The major research interests of Dr. Zhang's laboratory focus on the molecular pathology of cancer development, progression, and treatment.

They use molecular biology, protein biochemistry, cell biology, and animal models to address related questions mainly in blood cells. Currently, their work is in two separate areas: 1) transcription factor AML1 and its fusion protein AML1-ETO in normal blood cell differentiation, and in leukemia development, 2) modification by a ubiquitin like molecule – ISG15 and ISG15 specific protease UBP43 in interferon signaling and in cancer. During the process of differentiation, pluripotent stem cells proliferate and gradually change their pattern of gene expression to become lineage specific progenitor cells and eventually become terminally differentiated cells.

A frequent finding in leukemia is a consistent chromosome translocation resulting in abnormal fusion proteins. For example, 8;21 translocation is found in 15% of patients with de novo acute myeloid leukemia and generates a fusion protein AML1-ETO. They have demonstrated that AML1, in association with two other transcription factors - PU.1 and CCAAT enhancer binding protein (C/EBP), plays a critical role in directing the expression of myeloid specific genes. Furthermore, using various mouse models, including gene knock-in, transgenic, and retrovirus mediated bone marrow transplantation approaches, Dr. Zhang and her colleagues have demonstrated that AML1-ETO dominantly blocks AML1 in definitive blood cell production and AML1-ETO plays a critical role in leukemia development in the presence of additional mutations. They have also cloned a novel member of the deubiquitylating enzymes, UBP43, from AML1-ETO knock-in mice. Like phosphorylation and dephosphorylation, ubiquitylation and deubiquitylation represent other mechanisms for protein modification. Our most recent work has demonstrated that UBP43 is the only currently known enzyme to remove a ubiquitin-like modifier – ISG15 from ISG15 conjugates. Unlike ubiquitin and other ubiquitin like modifiers, ISG15 is not present in lower eukaryotes, such as yeast, indicating it may be associated with specialized functions in higher eukaryotic cells, such as immune responses. Upon viral infection, bacterial infection, or other stress stimulations, ISG15 can be detected in cells both in free and in conjugated form (ISGylation).

The discovery of the function of UBP43 has provided a useful tool for the analysis of protein ISGylation. We have recently revealed that UBP43 deficient cells are hypersensitive to type I interferon treatment and several important signal transduction regulators, such as Stat1, Erk1/2, Jak1, and PLC, can be modified by ISG15.

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