Am J Cancer Res 2012;2(5):606-619
Original Article
Thyroid hormone receptor β suppresses SV40-mediated
tumorigenesis via novel nongenomic actions
Dong Wook Kim, Li Zhao, John Hanover, Mark Willingham, Sheue-yann Cheng
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute; Laboratory of Cell Biochemistry and
Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892 and Department of Pathology,
Wake Forest University, Winston-Salem, NC, 27157
Received August 7, 2012; accepted August 22, 2012; Epub August 23, 2012; Published September 15, 2012
Abstract: Accumulated evidence suggests that thyroid hormone receptor β (TRβ) could function as a tumor suppressor, but the
detailed mechanisms by which TRβ inhibits tumorigenesis are not fully understood. The present studies explored the
mechanisms by which TRβ acted to inhibit thyroid tumor development mediated by simian virus-40 (SV40). In mouse xenograft
models, SV40 large T antigen (SV40Tag)-immortalized human thyroid epithelial (HTori) cells rapidly induced tumors, but the
tumor development was totally blocked by TRβ stably expressed in HTori cells. Previous studies showed that the SV40Tag
oncoprotein binds to and inactivates tumor suppressors p53 and retinoblastoma protein (Rb), thereby inducing tumorigenesis.
Here we showed that one of the mechanisms by which TRβ suppressed tumor development was by competing with p53 and Rb
for binding to SV40Tag. The interaction of TRβ with SV40Tag led to reactivation of Rb to inhibit cell cycle progression. TRβ-
SV40Tag interaction also resulted in reactivating p53 to increase the expression of Pten, thus attenuating PI3K-AKT signaling to
decrease cell proliferation and to induce apoptosis. The present study uncovered a novel action of TRβ as a tumor suppressor
initiated via interfering with the recruitment of Rb and p53 by SV40Tag oncoprotein through protein-protein interaction, thereby
acting to block tumor development. (AJCR0000141).
Keywords: Thyroid hormone receptor, tumor suppressor, tumorigenesis, thyroid hormone, xenograft models
Address all correspondence to:
Sheue-yann Cheng, PhD
Gene Regulation Section
Laboratory of Molecular Biology
CCR, NCI, NIH, Bethesda, MD, USA.
E-mail: chengs@mail.nih.gov
Original Article
Thyroid hormone receptor β suppresses SV40-mediated
tumorigenesis via novel nongenomic actions
Dong Wook Kim, Li Zhao, John Hanover, Mark Willingham, Sheue-yann Cheng
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute; Laboratory of Cell Biochemistry and
Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892 and Department of Pathology,
Wake Forest University, Winston-Salem, NC, 27157
Received August 7, 2012; accepted August 22, 2012; Epub August 23, 2012; Published September 15, 2012
Abstract: Accumulated evidence suggests that thyroid hormone receptor β (TRβ) could function as a tumor suppressor, but the
detailed mechanisms by which TRβ inhibits tumorigenesis are not fully understood. The present studies explored the
mechanisms by which TRβ acted to inhibit thyroid tumor development mediated by simian virus-40 (SV40). In mouse xenograft
models, SV40 large T antigen (SV40Tag)-immortalized human thyroid epithelial (HTori) cells rapidly induced tumors, but the
tumor development was totally blocked by TRβ stably expressed in HTori cells. Previous studies showed that the SV40Tag
oncoprotein binds to and inactivates tumor suppressors p53 and retinoblastoma protein (Rb), thereby inducing tumorigenesis.
Here we showed that one of the mechanisms by which TRβ suppressed tumor development was by competing with p53 and Rb
for binding to SV40Tag. The interaction of TRβ with SV40Tag led to reactivation of Rb to inhibit cell cycle progression. TRβ-
SV40Tag interaction also resulted in reactivating p53 to increase the expression of Pten, thus attenuating PI3K-AKT signaling to
decrease cell proliferation and to induce apoptosis. The present study uncovered a novel action of TRβ as a tumor suppressor
initiated via interfering with the recruitment of Rb and p53 by SV40Tag oncoprotein through protein-protein interaction, thereby
acting to block tumor development. (AJCR0000141).
Keywords: Thyroid hormone receptor, tumor suppressor, tumorigenesis, thyroid hormone, xenograft models
Address all correspondence to:
Sheue-yann Cheng, PhD
Gene Regulation Section
Laboratory of Molecular Biology
CCR, NCI, NIH, Bethesda, MD, USA.
E-mail: chengs@mail.nih.gov
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American Journal of Cancer Research
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