ARTICLES

Cell Research (2006)16:780-796
© 2006 IBCB, SIBS, CAS All rights reserved 1001-0602/06 $ 30.00
www.nature.com/cr

Transcription of the putative tumor suppressor gene HCCS1 requires binding of ETS-2 to its consensus near the transcription start site

Jing De Zhu, Qi Fei, Peng Wang, Fei Lan, Da Qin Mao, Hong Yu Zhang, Xue Biao Yao

¹Laboratory of Cancer Epigenetics and Gene Therapy, The State-Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, LN 2200/25, Xietu Road, Shanghai 200032, China; ²School of Life Sciences, Zhejiang Science and Technology University, Xiasha University District, Hangzhou, Zhejiang 310018, China; ³Laboratory of Cellular Dynamics, University of Science and Technology of China, Hefei 230027, China

Correspondence: Jing De Zhu Tel: +86-21-64224285 E-mail: zhujingde@yahoo.com Received 13 Jun 2006; revised 31 Jul 2006; accepted 4 Aug 2006; published online 5 Sep 2006

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The hepatocellular carcinoma suppressor 1 (HCCS1) gene was identified by both positional cloning from a predominant region of loss of heterozygosity (17p13.3) in liver cancer and by functional screening for genes affecting cell proliferation in large-scale transfection assays. Its overexpression results in inhibition of cell proliferation in cell culture and tumor growth in nude mice. To understand its transcription regulation, the promoter architecture has been dissected in detail. The major start of transcription was mapped by primer extension to a C residue, 177 nucleotides upstream of the ATG codon. By assessing the promoter activity of a set of linker-scanning mutants of the minimal promoter (¨C60 to +148 region) in a transient transfection assay, we found that the +1 to + 40 region is critical to HCCS1 gene transcription, containing binding sites for transcription factors NF-κB (¨C21 to +7 and +40 to +26), p53 (+29 to +9) and ETS (+4 to +20 and +23 to +39). Biochemical and molecular analyses revealed that the ETS transcription factors ETS-2 and Elf-1 bind to the two ETS sites in situ and contribute significantly to the transcriptionally active state of the HCCS1 gene, while NF-κB, p53 and two other members of the ETS family (ETS-1 and NERF2) appear to play little role. Our observations provide insight into the mechanistic aspects of HCCS1 transcription regulation.

Cell Research (2006) 16:780-796. doi: 10.1038/sj.cr.7310092; published online 5 Sep 2006

Keywords: HCCS1 gene, transcription regulation, ETS, p53, NF-κB