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Phone: 301-496-4280
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Email: sycheng@helix.nih.gov
Biography:
Dr. Cheng is the Chief of the Gene Regulation
Section, Laboratory of Molecular Biology, Division of Basic Sciences. She
received her Ph.D. from the University of California, San Francisco Medical
Center and her postdoctoral training with Dr. Elwood Jensen at the Ben May
Laboratory for Cancer Research, University of Chicago and with Drs. Hans
Cahmann and Jacob Robbins at NIDDK. She served as a president and chairperson
on various committees for several professional societies. Currently, she is a
member of the Editorial Board for the Journal of Biomedical Sciences and
Thyroid. She is a recipient of the NIH Award of Merit for outstanding
achievements and the Scientific Achievement Award from the Chinese Medical and
Health Association.
Curriculum Vitae
Research:
The thyroid hormone, 3,5,3'-triiodo-L-thyronine
(T3) is essential for growth, development and differentiation. Our goal is to
understand the molecular mechansims by which T3 mediates its pleiotropic
effects. Our studies have particular clinical relevance to a human genetic
disease, thyroid hormone resistance syndrome. Furthermore, we hope to shed
light on the role of thyroid hormones in breast cancer.
Elucidation of the Structure, Function and Regulation of Thyroid
Hormone Receptors (TRs)
Recent studies have indicated that the pleiotropic effect of T3 is mediated
through the interaction of T3 with TRs. To understand the molecular basis of
the T3-dependent gene regulating activity of TRs, we studied the structure of
the hormone binding domain of the human TR subtype b1 (h-TRb1). We proposed
a tertiary structure of the hormone binding domain of h-TRb1 and found that
binding of T3 induces conformational changes which could serve as the signal
to affect the interaction of h-TRb1 with the hormone response elements of T3
target genes (Cheng, 1995). We have identified two specific T3 interaction
regions in h-TRb1 which could mediate the T3-dependent transcriptional
activity. One region is located at the C-terminal five-amino acid segment
which could be involved in T3-dependent intermolecular interaction with the
bridging factors/mediator of the transcriptional machinery (Bhat et al, 1995).
The other region is located in E248-V256 which could be in direct contact with
the nearby DNA binding domain, thus affecting the interaction of the DNA
binding domain with T3 target genes. We have shown that the transcriptional
activity of h-TRb1 is regulated by phosphorylation. The T3-dependent
phosphorylation leads to structural modifications which could affect its
interaction with the components of transcriptional machinery (Bhat et al, 1994).
Delineation of the Molecular Basis of Thyroid Hormone Resistance Syndrome
The manifestation of thyroid hormone resistance syndrome is due to mutations
in the hormone binding domain of TRb gene, resulting in interference of the
functions of the wild type TRs in a dominant negative fashion. The dominant
negative action of the mutant TR is modulated in a cell-type dependent manner
(Wong et al 1995). Recently, in collaboration with Wong and Weintraub of
NIDDK, we have developed a transgenic mouse model of thyroid hormone resistance
syndrome to better understand the molecular basis of this human disease.
Identification of the Role of Thyroid Hormones in Breast Cancer
We found that h-TRb1 and the tumor suppressor p53 are coexpressed in several
breast cancer cell lines. Further studies indicate that the transcriptional
activity of TRs is repressed by p53, but is not affected by the mutant p53,
suggesting that one of the mechanisms by which p53 regulates cell proliferation
could be mediated by TRs. The findings that TRs interact with p53 implicate
the important role of TRs in the progression of breast cancer.
Recent Publications:
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Cheng SY J Biomed Sci 1995;2:77-89.
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Bhat MK et al. Biochemistry 1995;34:10591-10599.
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Wong R et al. Mol Med 1995;1:306-319.
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Bhat MK et al. Proc Natl Acad Sci USA 1994;91:7927-7931.
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