Jian-Hua Zhang, Ph.D.

Research Goal

Understanding the molecular interactions of the CDC73 tumor suppressor may shed light on the pathway to malignancy in the parathyroid and other tissues and help identify biomarkers and/or targets in cancer development that can be used in clinical diagnosis and therapy. In addition, better understanding of the functional interactions and signaling properties of the Gβ5/R7RGS/R7BP in neurons and neuroendocrine tissues may help elucidate its potential role in human neurologic and metabolic disease, including disorders of neurodevelopmental delay.

Current Research

Current projects include: (1) elucidation of the molecular signaling networks of the tumor suppressor gene CDC73/Hyrax, using mammalian and Drosophila models; and (2) studies about the physiological significance and molecular functions of G◊55-R7RGS-R7BP complex using genetically modified mice, primary neuronal cell cultures, and brain tissue cultures.

Heterotrimeric G proteins (Gα, Gβ, and Gγ) relay extracellular signals from membrane-integrated G-protein-coupled receptors (GPCR) to intracellular downstream effectors in eukaryotic cells. G protein β5 (Gβ5) is the fifth member of the Gβs, but it forms complexes with the R7 subfamily of Regulator of G protein Signaling (R7RGS) rather than Gs. The four members of the R7RGS (RGS6, 7, 9, and 11), and the GTPase-activating protein, also bind to R7BP (or R9AP in retina) to facilitate membrane association and signal transduction. The Gβ5 subunit stabilizes R7RGS and R9AP in retina to regulate phototransduction and light responses of retinal bipolar cells. However, it is less understood how the Gβ5/R7RGS/R7BP complex functions in brain, peripheral neurons, and neuroendocrine tissues where they are expressed predominantly. Recent studies revealed that lack of the Gβ5 complex impairs neuron development and function in mice by dysregulation of multiple neuron-specific genes. As a result, the Gβ5 knockout mice displayed a range of abnormal phenotypes, including hyperactivity, impaired motor coordination and learning abilities, and changed metabolism. These results suggested that the Gβ5/R7RGS/R7BP complex plays important roles in both neurological and metabolic systems of mice.

The tumor suppressor gene CDC73 (formerly called HRPT2) encodes parafibromin, a component of the PAF1 transcription complex associated with RNA polymerase II. Mutations of CDC73 in humans have been linked to the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid carcinoma. Using a trio-gene genetic screening method in the fly, we identified more than 20 genes genetically interacting with the hyrax (hyx) or lobe gene, the fly homologues of the mammalian CDC73, and akt1s1 genes, respectively. Some of the identified genes are transcriptional targets of CDC73/hyx and are associated with the well-characterized pI3K-AKT-mTOR and Wnt-β-catenin-Axin signaling pathways. As an example, the expression of 4E-BP3 (Thor in the fly), a novel transcription target of the CDC73/hyx gene, is regulated by nutrient availability in an mTOR-dependent manner in both flies and the cultured human mononuclear leukocytes. The 4E-BP3 expression is altered in CDC73 heterozygous patients and is a potential marker to predict HRTP2/CDC73 haploinsufficiency in a parathyroid cancer syndrome.

Applying our Research

We expect the CDC73 tumor suppressor study will facilitate the development of more effective diagnostic and therapeutic tools for parathyroid and other malignancies. Functional characterization of the Gβ5/R7RGS/R7BP complex may help us understand and treat new and emerging neurological and neuroendocrinal diseases.

Need for Further Study

The high throughput analyses of transcriptome and proteome of both clinical samples and animal models are needed to advance the current studies in this field.

Research in Plain Language

Our lab is currently working on two independent projects. The first project is to understand the molecular roles of the CDC73 tumor suppressor gene. Defects of the CDC73 gene are strongly linked to parathyroid cancer and tumors in other tissues, including the jaw, kidneys, and uterus. Mice missing the CDC73 gene die at early embryonic stage. These findings suggest that the CDC73 gene is critical for both development and progression to malignancy in parathyroid tumors. Using mainly fruit fly and mammalian systems, we are trying to shed light on the genetic and molecular interacting networks associated with the CDC73 gene in its tumor-suppression function.

The second project is to determine the biological significance and molecular functions of a special set of proteins that form a complex and work together to help cells communicate with each other. These complexes are embedded in the cell membranes of brain cells (neurons) and specialized neurons that communicate with the body’s glandular system, or endocrine system. We studying the communication process of these neurons, specifically how they are impacted by signals from a specific protein in the complex called Gβ5. We’ve learned, for instance, that mice lacking this protein are severely developmentally delayed and show noticeable abnormal neuron development, but just how Gβ5 impacts cell-to-cell communication via the endocrine system is poorly understood. Our project aims to learn more about the basic molecular interactions and cellular functions of this signaling complex—which is found across different species—to help medical scientists treat neuronal and endocrine diseases.