Dataset Information

The TP53-Induced Glycolysis and Apoptosis Regulator mediates cooperation between HTLV-1 p30^II and the retroviral oncoproteins Tax and HBZ and is highly expressed in an in vivo xenograft model of HTLV-1-induced lymphoma.

ABSTRACT: The human T-cell leukemia virus type-1 (HTLV-1) is an oncoretrovirus that infects and transforms CD4+ T-cells and causes adult T-cell leukemia/lymphoma (ATLL) -an aggressive lymphoproliferative disease that is highly refractive to most anticancer therapies. The HTLV-1 proviral genome encodes several regulatory products within a conserved 3' nucleotide sequence, known as pX; however, it remains unclear how these factors might cooperate or dynamically interact in virus-infected cells. Here we demonstrate that the HTLV-1 latency-maintenance factor p30^II induces the TP53-induced glycolysis and apoptosis regulator (TIGAR) and counters the oxidative stress, mitochondrial damage, and cytotoxicity caused by the viral oncoproteins Tax and HBZ. The p30^II protein cooperates with Tax and HBZ and enhances their oncogenic potential in colony transformation/foci-formation assays. Further, we have shown that TIGAR is highly expressed in HTLV-1-induced tumors associated with oncogene dysregulation and increased angiogenesis in an in vivo xenograft model of HTLV-1-induced T-cell lymphoma. These findings provide the first evidence that p30^II likely collaborates as an ancillary factor for the major oncoproteins Tax and HBZ during retroviral carcinogenesis.

SUBMITTER: Hutchison T

PROVIDER: S-EPMC6082153 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Publications

The TP53-Induced Glycolysis and Apoptosis Regulator mediates cooperation between HTLV-1 p30<sup>II</sup> and the retroviral oncoproteins Tax and HBZ and is highly expressed in an in vivo xenograft model of HTLV-1-induced lymphoma.

Hutchison Tetiana T Malu Aditi A Yapindi Laçin L Bergeson Rachel R Peck Kendra K Romeo Megan M Harrod Carolyn C Pope Jordan J Smitherman Louisa L Gwinn Wesleigh W Ratner Lee L Yates Courtney C Harrod Robert R

Virology 20180526

The human T-cell leukemia virus type-1 (HTLV-1) is an oncoretrovirus that infects and transforms CD4+ T-cells and causes adult T-cell leukemia/lymphoma (ATLL) -an aggressive lymphoproliferative disease that is highly refractive to most anticancer therapies. The HTLV-1 proviral genome encodes several regulatory products within a conserved 3' nucleotide sequence, known as pX; however, it remains unclear how these factors might cooperate or dynamically interact in virus-infected cells. Here we demo ...[more]

PMID: 29777913

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Project description:Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus responsible for adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a progressive neurodegenerative disease. Regulation of viral gene expression plays a key role in viral persistence and pathogenesis. However, the molecular mechanisms underlying this fine-tuned regulation remain poorly understood. Little is known regarding RNA chemical modifications of HTLV-1 RNA and how these affect viral biology and disease development. Post-transcriptional chemical modification of RNA is common in eukaryotes, with N6-methyladenosine (m6A) being the most prevalent. In this study, we investigated the role of m6A RNA modifications on HTLV-1 gene expression. Using MeRIP-Seq, we mapped the sites of m6A modification to the 3' end of the viral genome. We found HTLV-1 RNA, as well as viral oncogene transcripts tax and hbz, contained m6A modifications. m6A-depletion in HTLV-1-transformed cells decreased sense-derived viral genes (Tax, Gag, and Env) and increased antisense-derived Hbz expression. Tax and hbz transcripts were bound by reader proteins YTHDF1 and YTHDC1 in a panel of HTLV-1 T-cell lines. Using expression vectors and shRNA-mediated knockdown, we found that YTHDF1 had opposing effects on viral gene expression, decreasing sense-derived viral genes and increasing antisense-derived Hbz. Upon further study, the YTHDF1 effects on tax abundance were dependent on tax m6A deposition. The nuclear m6A reader protein YTHDC1 affected the abundance of both sense- and antisense-derived viral transcripts and specifically enhanced the nuclear export of tax transcript. Collectively, our results demonstrate global m6A levels and m6A reader proteins YTHDF1 and YTHDC1 regulate HTLV-1 gene expression.IMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) persistence and pathogenesis are controlled through tight regulation of viral gene expression. The fate of RNA can be controlled by epigenetic modifications that impact gene expression without altering the DNA sequence. Our study details the impact of N6-methyladenosine (m6A) RNA chemical modifications on HTLV-1 gene expression. We found that reductions in global m6A levels affected viral gene expression, decreasing Tax and other sense-derived viral genes, whereas increasing the antisense-derived Hbz. Our results suggest the oncogenic viral transcripts, tax and hbz, are m6A-modified in cells. We found that these viral RNA modifications are interpreted by reader proteins YTHDF1 and YTHDC1, which dictate the fate of the viral RNA. Understanding HTLV-1 RNA chemical modifications offers potential insights into novel therapeutic strategies for HTLV-1-associated diseases.

Dataset Information

The TP53-Induced Glycolysis and Apoptosis Regulator mediates cooperation between HTLV-1 p30^II and the retroviral oncoproteins Tax and HBZ and is highly expressed in an in vivo xenograft model of HTLV-1-induced lymphoma.

Publications

The TP53-Induced Glycolysis and Apoptosis Regulator mediates cooperation between HTLV-1 p30<sup>II</sup> and the retroviral oncoproteins Tax and HBZ and is highly expressed in an in vivo xenograft model of HTLV-1-induced lymphoma.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

The TP53-Induced Glycolysis and Apoptosis Regulator mediates cooperation between HTLV-1 p30II and the retroviral oncoproteins Tax and HBZ and is highly expressed in an in vivo xenograft model of HTLV-1-induced lymphoma.

Publications

The TP53-Induced Glycolysis and Apoptosis Regulator mediates cooperation between HTLV-1 p30<sup>II</sup> and the retroviral oncoproteins Tax and HBZ and is highly expressed in an in vivo xenograft model of HTLV-1-induced lymphoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The TP53-Induced Glycolysis and Apoptosis Regulator mediates cooperation between HTLV-1 p30^II and the retroviral oncoproteins Tax and HBZ and is highly expressed in an in vivo xenograft model of HTLV-1-induced lymphoma.