HTLV-1 bZIP factor impedes the menin tumor suppressor and upregulates JunD-mediated transcription of the hTERT gene

Borowiak, Malgorzata; Kuhlmann, Anne-Sophie; Girard, Sophie; Gazzolo, Louis; Mesnard, Jean-Michel; Jalinot, Pierre; Dodon, Madeleine Duc

doi:10.1093/carcin/bgt221

Cited by 23 publications

(19 citation statements)

References 46 publications

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“…Therefore, it is reasonable and significant to reveal the molecular mechanisms of the tumor-specific expression and activation of hTERT. Various cellular factors, including transcription factors and some intracellular signaling molecules, have been confirmed to be able to regulate hTERT expression in cancer cells by binding to hTERT promoter [ 15 - 17 , 35 - 37 ]. The aim of our study was to understand the molecular mechanism of transcriptional regulation for the observed increased expression of hTERT in non-small cell lung cancer cells and further assess its role in non-small cell lung cancer tumorigenesis and development.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional coactivator CBP upregulates hTERT expression and tumor growth and predicts poor prognosis in human lung cancers

Guo

Dai

et al. 2014

Oncotarget

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Upregulated expression and activation of human telomerase reverse transcriptase (hTERT) is a hallmarker of lung tumorigenesis. However, the mechanism underlying the aberrant hTERT activity in lung cancer cells remains poorly understood. In this study, we found the transcriptional co-activator CBP as a new hTERT promoter-binding protein that regulated hTERT expression and tumor growth in lung adenocarcinoma cells using a biotin-streptavidin-bead pulldown technique. Chromatin immunoprecipitation assay verified the immortalized cell and tumor cell-specific binding of CBP on hTERT promoter. Overexpression of exogenous CBP upregulated the expression of the hTERT promoter-driven luciferase and endogenous hTERT protein in lung cancer cells. Conversely, inhibition of CBP by CBP-specific siRNA or its chemical inhibitor repressed the expression of hTERT promoter-driven luciferase and endogenous hTERT protein as well as telomerase activity. Moreover, inhibition of CBP expression or activity also significantly reduced the proliferation of lung cancer cells in vitro and tumor growth in an xenograft mouse model in vivo. Immunohistochemical analysis of tissue microarrays of lung cancers revealed a positive correlation between CBP and hTERT. Importantly, the patients with high CBP and hTERT expression had a significantly shorter overall survival. Furthermore, CBP was found to interact with and acetylate transactivator Sp1 in lung cancer cells. Inhibition of CBP by CBP-specific siRNA or its chemical inhibitor significantly inhibited Sp1 acetylation and its binding to the hTERT promoter. Collectively, our results indicate that CBP contributes to the upregulation of hTERT expression and tumor growth, and overexpression of CBP predicts poor prognosis in human lung cancers.

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Section: Discussionmentioning

confidence: 99%

Transcriptional coactivator CBP upregulates hTERT expression and tumor growth and predicts poor prognosis in human lung cancers

Guo

Dai

et al. 2014

Oncotarget

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“…HBZ has been reported to directly or indirectly interact with the following proteins that are essential in CREB-dependent cellular proliferation: CREB, CBP, ATF-1, and ATF-3 [ 185 , 186 , 187 , 188 ]. Additionally, HBZ interacts with the Jun family of transcription factors, JunB, JunD, and c-Jun [ 189 , 190 , 191 ]. The combined activities of Tax and HBZ are essential for cellular proliferation.…”

Section: Monoclonal Expansion Of Htlv-1 Infected Cells and Leukemomentioning

confidence: 99%

Molecular Studies of HTLV-1 Replication: An Update

Martin

Maldonado

Mueller

et al. 2016

Viruses

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Human T-cell leukemia virus type 1 (HTLV-1) was the first human retrovirus discovered. Studies on HTLV-1 have been instrumental for our understanding of the molecular pathology of virus-induced cancers. HTLV-1 is the etiological agent of an adult T-cell leukemia (ATL) and can lead to a variety of neurological pathologies, including HTLV-1-associated-myelopathy/tropical spastic paraparesis (HAM/TSP). The ability to treat the aggressive ATL subtypes remains inadequate. HTLV-1 replicates by (1) an infectious cycle involving virus budding and infection of new permissive target cells and (2) mitotic division of cells harboring an integrated provirus. Virus replication initiates host antiviral immunity and the checkpoint control of cell proliferation, but HTLV-1 has evolved elegant strategies to counteract these host defense mechanisms to allow for virus persistence. The study of the molecular biology of HTLV-1 replication has provided crucial information for understanding HTLV-1 replication as well as aspects of viral replication that are shared between HTLV-1 and human immunodeficiency virus type 1 (HIV-1). Here in this review, we discuss the various stages of the virus replication cycle—both foundational knowledge as well as current updates of ongoing research that is important for understanding HTLV-1 molecular pathogenesis as well as in developing novel therapeutic strategies.

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“…HBZ can increase hTERT expression in a JunD and SP-1-dependent manner while HBZ and c-Jun complexes exert a negative effect [102] . In addition, HBZ can antagonize Menin-mediated recruitment of HDAC and inhibition of JunD by interacting with and recruiting p300 instead to the hTERT promoter [103] . An additional negative regulator of the hTERT promoter, the T-cell acute lymphoblastic leukemia 1 protein (Tal1), was also found to be repressed by HBZ [104] .…”

Section: Introductionmentioning

confidence: 99%

Multiple Pathways Control the Reactivation of Telomerase in HTLV-I-Associated Leukemia

Bellon

Nicot

2015

IJCO

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While telomerase (hTERT) activity is absent from normal somatic cells, reactivation of hTERT expression is a hallmark of cancer cells. Telomerase activity is required for avoiding replicative senescence and supports immortalization of cellular proliferation. Only a minority of cancer cells rely on a telomerase-independent process known as alternative lengthening of telomeres, ALT, to sustain cancer cell proliferation. Multiple genetic, epigenetic, and viral mechanisms have been found to de-regulate telomerase gene expression, thereby increasing the risk of cellular transformation. Here, we review the different strategies used by the Human T-cell leukemia virus type 1, HTLV-I, to activate hTERT expression and stimulate its enzymatic activity in virally infected CD4 T cells. The implications of hTERT reactivation in HTLV-I pathogenesis and disease treatment are discussed.

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HTLV-1 bZIP factor impedes the menin tumor suppressor and upregulates JunD-mediated transcription of the hTERT gene

Cited by 23 publications

References 46 publications

Transcriptional coactivator CBP upregulates hTERT expression and tumor growth and predicts poor prognosis in human lung cancers

Transcriptional coactivator CBP upregulates hTERT expression and tumor growth and predicts poor prognosis in human lung cancers

Molecular Studies of HTLV-1 Replication: An Update

Multiple Pathways Control the Reactivation of Telomerase in HTLV-I-Associated Leukemia

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