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Sheue-yann Cheng, Ph.D.

Laboratory of Molecular Biology Head, Gene Regulation Section Senior Investigator Bldg. 37, Room 5128 NCI-Bethesda Bethesda, MD 20892 Phone:   301-496-4280 Fax:   301-480-9676 E-Mail:   chengs@mail.nih.gov

Biography

Dr. Sheue-yann Cheng obtained her Ph.D. from the University of California, San Francisco Medical Center. She received her postdoctoral training at the University of Chicago and the National Institute of Diabetes and Digestive and Kidney Diseases. She joined the NCI as a senior investigator in 1979 and was promoted to section chief in 1991. Dr. Cheng is a recipient of the NIH Merit Award for outstanding achievements, the Scientific Achievement Award from the Chinese Medical and Health Association, the Charles Harkin Award of the NCI, the Sidney H. Ingbar Distinguished Lectureship Award of the American Thyroid Association, and the Abbott Thyroid Research Clinical Fellowship Mentor Award of The Endocrine Society. Dr. Cheng describes her current research as follows.

Research

Thyroid Hormone Receptor Mutants: Molecular Actions and Roles in Disease
Thyroid hormone receptors (TRs) mediate the biological activities of the thyroid hormone (T3) in growth, development, and differentiation and in maintenance of metabolic homeostasis. There are two TR genes, alpha and beta, located on human chromosomes 17 and 3, respectively. Alternative splicing of the primary transcripts gives rise to four major T3-binding isoforms: alpha 1, beta 1, beta 2, and beta 3. The expression of TR isoforms is tissue-dependent and developmentally regulated.

Given the critical roles of TRs, it is reasonable to expect that mutations of TRs could have deleterious consequences. Indeed, mutations of the TRbeta gene are known to cause a human genetic disease, resistance to thyroid hormone (RTH). However, whether mutations of the TRbeta gene can cause other human diseases is not clear. We therefore have created and exploited genetically engineered mice as models to understand the in vivo actions of mutated TRs and their roles in human disease. These mouse models are being used to develop potential treatment strategies.

The TRbetaPV mouse is a model of the human disease called resistance to thyroid hormone
RTH is a disease caused by mutations of the TRbeta gene. A mutation derived from an RTH patient at NIH (TRbetaPV) was targeted to the TRbeta gene locus by using homologous recombination and the Cre-lox system (TRbetaPV mouse). We found TRbetaPV mice faithfully reproduced RTH in humans. This landmark study addressed several critical, clinically relevant issues that previously could not be studied. We showed unequivocally that RTH symptoms are caused by the dominant negative action of mutant TRbeta in vivo and that the variable phenotypic expression in RTH patients is dictated by the tissue-dependent abundance of TRbeta and TRalpha isoforms. We also found that the dominant negative activity of TRbeta mutants is modulated in vivo by multiple combinatorial factors including members of the p160 coactivator family. Recently, using comprehensive gene profiling in three T3 target-tissues, we made the novel discovery that the 'change-of-function' of TRbeta mutants also contributes to the manifestation of RTH. With these mouse-model findings, not only can better treatments for RTH be developed but also better management of other receptor diseases can be envisioned.

The TRbeta^PV/PVmouse is a model of thyroid carcinogenesis
We made the remarkable discovery that TRbeta^PV/PV but not TRbeta^PV/+, mice spontaneously develop metastatic follicular thyroid carcinoma similar to human thyroid cancer. Previously, the lack of valid mouse models with metastatic spread had impeded understanding of the molecular events of thyroid cancer invasion and metastasis. Our mouse model offers an unprecedented opportunity for investigators to understand the molecular genetics underlying thyroid carcinogenesis, to identify signature genes for diagnosis, and to uncover possible molecular targets for treatment of thyroid cancer. Indeed, we have shown for the first time that complex alterations of genes and multiple signaling pathways contribute to thyroid carcinogenesis. Importantly, we have also found that the expression and the activity of the peroxisome proliferator-activated receptor gamma (PPARgamma) is repressed during thyroid carcinogenesis. Because PPARgamma has anti-proliferative activity, these results raise the possibility that activation of PPARgamma activity by its agonists could inhibit the progression of thyroid carcinogenesis. Indeed, recently, we treated TRbeta^PV/PV mice with rosiglitazone, a PPARgamma agonist, and found that it significantly delayed the progression of thyroid carcinogenesis by decreasing cell proliferation and inducing apoptosis. These preclinical findings suggest that PPARgamma could be tested as a therapeutic target in human thyroid follicular carcinoma, and they validate the usefulness of TRbeta^PV/PV mice as a platform for translation of research from the bench to bedside. Additional molecular targets are currently been sought by using this preclinical mouse model.

The TRbeta^PV/PV mouse is a model of pituitary tumorigenesis
TSHomas are pituitary tumors that constitutively secrete thyroid stimulating hormone (TSH). TSHomas are usually large at diagnosis and are associated with headaches, visual field disturbances, and deficiency in other pituitary hormones. Because diagnosis occurs late in the natural course, curative surgical resection of TSHomas remains under 50%. The molecular genetics underlying TSHomas are not well understood. We discovered that TRbeta^PV/PV mice spontaneously develop TSHomas, thus providing the first mouse model to elucidate molecular genetic events underlying tumorigenesis of the pituitary and to identify potential molecular targets for diagnosis and treatment. Indeed, we found that the significantly increased TSH alone in TRbeta^PV/PV mice is not sufficient to induce TSHomas. The increased expression of cyclin D1, at both the mRNA and protein levels, propels the thyrotropes to proliferate via the cyclin-dependent kinase (CDK)/retinoblastoma (Rb)/E2F pathway. The activation of cyclin D1 expression is via a novel mechanism of tethering of TRbeta PV mutant to the cAMP response element binding protein (CREB) through physical interaction of PV with CREB on the cyclin D1 promoter. Thus the in vivo evidence suggests that mutation of the TRb gene is one of the genetic events mediating the pathogenesis of this disease. Other genetic events underlying the development of TSHomas are currently been explored by using the TRbeta^PV/PV mouse model.

The TRalpha1PV mouse is a model to elucidate the genetic basis of human dwarfism
The intriguing observation that no mutations of the TRalpha gene have ever been identified in RTH patients has perplexed investigators for years. This absence raised the fundamental issue of whether mutations of the TRalpha gene are lethal or can cause other human diseases. We therefore targeted the PV mutation to the TRalpha gene locus (TRalpha1PV mice). The successful creation of the TRalpha knock-in mutant mouse unequivocally resolved this fundamental issue. The mutation of one allele of the TRalpha gene is not lethal, but it does result in dwarfism and other abnormalities that are clearly distinct from the RTH shown in TRbetaPV mice. We also demonstrated that isoform-dependent abnormal regulation of T3 target genes underlies the distinct phenotypes of TRalpha1PV and TRbetaPV mice. Thus these two mutant mice provide a valuable tool to further dissect the molecular basis of isoform-dependent actions of mutant TRs in vivo.

Our collaborators are Mark Willingham, Wake Forest University School of Medicine, Winston-Salem, NC; Paul Meltzer, Human Genome Research Institute; and Bert O'Malley, Baylor College of Medicine, Houston, TX.

This page was last updated on 6/11/2008.