Reptin is required for the transcription of telomerase reverse transcriptase and over-expressed in gastric cancer

Molecular Cancer

Research

Magnus Björkholm¹  Dawei Xu¹  Li Zhao²  Jihui Jia²  Jiping Zeng³  Tiantian Liu³  Qiao Li³  Wenjuan Li³ 

[1] Department of Medicine, Division of Hematology, and Center for Molecular Medicine (CMM), Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden;Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine and School of Life Sciences, Shandong University, Jinan, PR China;Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine and School of Life Sciences, Shandong University, Jinan, PR China;Department of Medicine, Division of Hematology, and Center for Molecular Medicine (CMM), Karolinska University Hospital Solna and Karolinska Institutet, Stockholm, Sweden;

关键词: Gastric Cancer;    Gastric Cancer Cell;    Cervical Cancer Cell;    Cervical Cancer Cell Line;    Primary Gastric Cancer;   

DOI  :  10.1186/1476-4598-9-132

 received in 2009-10-05, accepted in 2010-05-30,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundTelomerase is activated in oncogenesis, which confers an immortal phenotype to cancer cells. The AAA + ATPase Reptin is required for telomerase biogenesis by maintaining telomerase RNA (hTER) stability and is aberrantly expressed in certain cancers. Given its role in chromatin remodeling and transcription regulation, we determined the effect of Reptin on the transcription of the telomerase reverse transcriptase (hTERT) gene, a key component of the telomerase complex and its expression in gastric cancer.ResultsKnocking down Reptin or its partner Pontin using small interfering RNA in gastric and cervical cancer cells led to significant decreases in hTERT mRNA, but hTERT promoter activity was inhibited in only Reptin-depleted cells. Reptin interacted with the c-MYC oncoprotein and its stimulatory effect on the hTERT promoter was significantly dependent on functional E-boxes in the promoter. Moreover, Reptin bound to the hTERT proximal promoter and the loss of the Reptin occupancy led to dissociation of c-MYC from the hTERT promoter in Reptin-depleted cells. Reptin inhibition dramatically impaired clonogenic potential of gastric cancer cells by inducing cell growtharrest and over-expression of Reptin was observed in primary gastric cancer specimens.ConclusionsThe hTERT gene is a direct target of Reptin, and hTERT transcription requires constitutive expression of Reptin and its cooperation with c-MYC. Thus, Reptin regulates telomerase at two different levels. This finding, together with the requirementof Reptin for the clonogenic potential of cancer cells and its over-expression in gastriccancer and other solid tumors, suggests that Reptin may be a putative therapeutic target.

【 授权许可】

Unknown   
© Li et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.