TGF-β and cancer: Is Smad3 a repressor of hTERT gene?

Li, He; Xu, Dakang; Toh, Ban‐Hock; Liu, Junping

doi:10.1038/sj.cr.7310023

Cited by 37 publications

(31 citation statements)

References 43 publications

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“…These include MAPK, transforming growth factor β (TGF-β) and NF-κB signalling pathways. Signals transmitted through MAPK family can increase or decrease hTERT transcription depending on different stimuli [51][52][53][54][55], whereas TGF-β inhibits hTERT gene transcription by Smad 3 signaling [56][57][58]. In addition, hTERT is also targeted for activation by several viral oncogenes including human papillomavirus (HPV) type-16 E6/E7 and simian virus 40 T antigens [59,60].…”

Section: Molecular Mechanisms Regulating Telomerase Activitymentioning

confidence: 99%

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

et al. 2006

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Nasopharyngeal carcinoma (NPC) is a common cancer in Southern China and Southeast Asia. The disease is a poorly differentiated carcinoma without effective cure, and the mechanism underlying its development remains largely unknown. Of several factors identified in NPC aetiology in recent years, Epstein-Barr virus (EBV) infection has emerged to be most important. In almost all NPC cells, EBV uses several intracellular mechanisms to cause oncogenic evolution of the infected cells. One such mechanism by which EBV infection induces cellular immortalization is believed to be through the activation of telomerase, an enzyme that is normally repressed but becomes activated during cancer development. Studies show that greater than 85% of primary NPC display high telomerase activity by mechanisms involving EBV infection, consistent with the notion that EBV is commonly involved in inducing cell immortalization. More recently, different EBV proteins have been shown to activate or inhibit the human telomerase reverse transcriptase gene, by modulating intracellular signalling pathways. These findings suggest a new model with a number of challenges towards our understanding, molecular targeting and therapeutic intervention in NPC.

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Section: Molecular Mechanisms Regulating Telomerase Activitymentioning

confidence: 99%

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

et al. 2006

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“…3A). These transcription factors themselves have been shown to play important oncogenic roles in tumorigenesis of many cancer types, including MM (27)(28)(29)(30)(31). We next cloned several fragments of the Gremlin promoter region into a promoterless luciferase expression vector pGL3Basic and transfected 293T cells with these constructs to examine luciferase activities (Fig.…”

Section: Activity Of the Gremlin Promoter In MM Cell Linesmentioning

confidence: 99%

The bone morphogenetic protein antagonist Gremlin is overexpressed in human malignant mesothelioma

et al. 2011

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Abstract.Gremlin is a member of the bone morphogenetic protein (BMP) antagonist family and its antagonistic effect is likely through direct binding to BMP proteins. As an antagonist of BMP, Gremlin plays a role in regulating organogenesis, body patterning and tissue differentiation. Recent studies have shown a deregulation of Gremlin in several types of human cancers. However, the role of Gremlin in human malignant mesothelioma (MM) is still unknown. In this study, we investigated the expression of Gremlin in human MM. We found that Gremlin mRNA and protein were both overexpressed in the majority of primary MM tissue samples that we examined. We also observed high level expression of the Gremlin gene in 4 of the 6 MM cell lines. Consistently, we found that the Gremlin promoter activity was significantly elevated in those MM cell lines expressing the Gremlin gene. On the other hand, no activity of the Gremlin promoter was detected in the two MM cell lines lacking Gremlin expression. Moreover, to examine the functional significance of the Gremlin overexpression in MM, we used shRNA to knock down Gremlin expression in MM cell lines expressing Gremlin and found that inhibition of Gremlin expression significantly suppressed proliferation of those MM cells. Taken together, our results suggest that the BMP antagonist Gremlin is overexpressed in MM and that aberrant activation of Gremlin may play a critical role in the tumorigenesis of human MM.

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“…We hypothesize that extracellular factors regulating cell differentiation exert an effect on hTERT gene expression, telomerase activity, and telomere maintenance through intracellular signaling. Studies from our laboratory and others show that TGF-h can induce an hTERT gene repression (30)(31)(32)(33)(34)(35). In the present study, we have examined effects of the BMP family on telomerase activity and telomere maintenance in cervical cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Bone Morphogenetic Protein-7 Inhibits Telomerase Activity, Telomere Maintenance, and Cervical Tumor Growth

Cassar

Pinto

et al. 2008

Cancer Research

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Telomere maintenance is critical in tumor cell immortalization. Here, we report that the cytokine bone morphogenetic protein-7 (BMP7) inhibits telomerase activity that is required for telomere maintenance in cervical cancer cells. Application of human recombinant BMP7 triggers a repression of the human telomerase reverse transcriptase (hTERT) gene, shortening of telomeres, and hTERT repression-dependent cervical cancer cell death. Continuous treatment of mouse xenograft tumors with BMP7, or silencing the hTERT gene, results in sustained inhibition of telomerase activity, shortening of telomeres, and tumor growth arrest. Overexpression of hTERT lengthens telomeres and blocks BMP7-induced tumor growth arrest. Thus, BMP7 negatively regulates telomere maintenance, inducing cervical tumor growth arrest by a mechanism of inducing hTERT gene repression. [Cancer Res 2008;68(22):9157-66]

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TGF-β and cancer: Is Smad3 a repressor of hTERT gene?

Cited by 37 publications

References 43 publications

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

The bone morphogenetic protein antagonist Gremlin is overexpressed in human malignant mesothelioma

Bone Morphogenetic Protein-7 Inhibits Telomerase Activity, Telomere Maintenance, and Cervical Tumor Growth

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