Abstract
Thanatos-associated proteins (THAPs) are zinc-dependent, sequence-specific DNA-binding factors involved in cell proliferation, apoptosis, cell cycle, chromatin modification and transcriptional regulation. THAP11 is the most recently described member of this human protein family. In this study, we show that THAP11 is ubiquitously expressed in normal tissues and frequently downregulated in several human tumor tissues. Overexpression of THAP11 markedly inhibits growth of a number of different cells, including cancer cells and non-transformed cells. Silencing of THAP11 by RNA interference in HepG2 cells results in loss of cell growth repression. These results suggest that human THAP11 may be an endogenous physiologic regulator of cell proliferation. We also provide evidence that the function of THAP11 is mediated by its ability to repress transcription of c-Myc. Promoter reporter assays indicate a DNA binding-dependent c-Myc transcriptional repression. Chromatin immunoprecipitations and EMSA assay suggest that THAP11 directly binds to the c-Myc promoter. The findings that expression of c-Myc rescues significantly cells from THAP11-mediated cell growth suppression and that THAP11 expression only slightly inhibits c-Myc null fibroblasts cells growth reveal that THAP11 inhibits cell growth through downregulation of c-Myc expression. Taken together, these suggest that THAP11 functions as a cell growth suppressor by negatively regulating the expression of c-Myc.
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Accession codes
Abbreviations
- ChIP:
-
chromatin immunoprecipitation
- EMSA:
-
electrophoretic mobility shift assay
- GFP:
-
green fluorescence GFP
- HCC:
-
hepatocellular carcinoma
- ODC:
-
ornithin decarboxylase
- RNAi:
-
RNA interference
- RT-PCR:
-
reverse transcription-PCR
- THAP:
-
Thanatos-associated protein
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Acknowledgements
We are grateful to Dr. Ken Kinzler and Bert Vogelstein (The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine) for providing c-Myc promoter luciferase reporter, and appreciate Dr. Tong-Chuan He for advice. This work was partially supported by the Special Funds for Major State Basic Research of China (2006CB910802), Chinese National Natural Science Fund for the Popularization of Science (30321003), Chinese National Nature Foundation Key Program Project (30630035), Chinese National Natural Science Foundation project (30480659, 30870958), and Beijing National Natural Science Foundation project.
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Zhu, CY., Li, CY., Li, Y. et al. Cell growth suppression by thanatos-associated protein 11(THAP11) is mediated by transcriptional downregulation of c-Myc. Cell Death Differ 16, 395–405 (2009). https://doi.org/10.1038/cdd.2008.160
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DOI: https://doi.org/10.1038/cdd.2008.160
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