Erythropoietin activates telomerase through transcriptional and posttranscriptional regulation in human erythroleukemic JAS-REN-A cells

Akiyama, Masaharu; Kawano, Takeshi; Mikami-Terao, Yoko; Agawa-Ohta, Miyuki; Ida, Hiroyuki

doi:10.1016/j.leukres.2010.11.002

Cited by 14 publications

(10 citation statements)

References 7 publications

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“…STAT5 is activated by IL-2 and has been shown to regulate the expression of various cyclins and CDKs required for cell cycle progression through the G1 and S phases (52). IL-2 signaling is also very important for maintaining Myc translation because Myc protein, but not mRNA, is lost when cytotoxic T cells (CTLs) are incubated with the JAK inhibitor tofacitinib (30,53). Preston et al showed that proinflammatory cytokines are required to maintain Myc protein abundance because, in T cells, these cytokines sustain expression of amino acid transporters, which in turn support the amino acid uptake required to replenish rapidly turning over Myc protein (30).…”

Section: Discussionmentioning

confidence: 99%

Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells

Tan

Knight

Sbarrato

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Global transcriptomic and proteomic analyses of T cells have been rich sources of unbiased data for understanding T-cell activation. Lack of full concordance of these datasets has illustrated that important facets of T-cell activation are controlled at the level of translation. We undertook translatome analysis of CD8 T-cell activation, combining polysome profiling and microarray analysis. We revealed that altering T-cell receptor stimulation influenced recruitment of mRNAs to heavy polysomes and translation of subsets of genes. A major pathway that was compromised, when TCR signaling was suboptimal, was linked to ribosome biogenesis, a rate-limiting factor in both cell growth and proliferation. Defective TCR signaling affected transcription and processing of ribosomal RNA precursors, as well as the translation of specific ribosomal proteins and translation factors. Mechanistically, IL-2 production was compromised in weakly stimulated T cells, affecting the abundance of Myc protein, a known regulator of ribosome biogenesis. Consequently, weakly activated T cells showed impaired production of ribosomes and a failure to maintain proliferative capacity after stimulation. We demonstrate that primary T cells respond to various environmental cues by regulating ribosome biogenesis and mRNA translation at multiple levels to sustain proliferation and differentiation.

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Section: Discussionmentioning

confidence: 99%

Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells

Tan

Knight

Sbarrato

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The phosphorylation of STAT5 was associated with P-gp and TERT expression, suggesting that STAT5 is involved in the control of these genes in primary AML cells and is implicated in drug resistance, as noted for CML cells. Moreover, erythropoietin induces telomerase activation and concomitant phosphorylation of STAT5, ERK, and Akt kinases in erythroleukemia cells 85 , 86 . In these cells, the erythropoietin-induced upregulation of telomerase mRNA is mediated by the STAT5-c-Myc axis, indicating a critical role of STAT5 in the pathogenesis of myeloid leukemias.…”

Section: The Role Of the Jak-stat Signaling Pathway In Telomerase Regmentioning

confidence: 99%

“…NFκB stimulated by Tax protein activates telomerase transcription via the binding of c-Myc and Sp1 to the TERT promoter in ATL tumor cells 62 . Furthermore, JAK2-STAT5 mediates TERT gene expression in EPO-stimulated erythroleukemia cells 85 and activates TERT mRNA transcription in cooperation with the PI3K/Akt/mTOR pathway in ATL cells 43 . Multiple signaling molecules and transcription factors interact with each other to form a complex network that regulates telomerase expression and activity.…”

Section: The Role Of the Jak-stat Signaling Pathway In Telomerase Regmentioning

confidence: 99%

The role of the JAK-STAT pathway and related signal cascades in telomerase activation during the development of hematologic malignancies

Kawauchi

2013

JAK-STAT

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Telomerase, comprising a reverse transcriptase protein (TERT) and an RNA template, plays a critical role during senescence and carcinogenesis; however, the mechanisms by which telomerase is regulated remain to be elucidated. Several signaling pathways are involved in the activation of TERT at multistep levels. The JAK-STAT pathway is indispensable for mediating signals through growth factor and cytokine receptors during the development of hematopoietic cells, and its activity is frequently upregulated in hematological malignancies. Here, we review the role of the JAK-STAT pathway and related signaling cascades in the regulation of telomerase in hematological malignancies.

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“…However, STAT5 was also reported to indirectly activate hTERT through c-Myc, another transcription activator of hTERT . In two different leukemic cell lines, erythropoietin (EPO) was proven to be a potent activator of telomerase and this was shown to be via the induction of the JAK2/STAT5/c-Myc axis, and in turn was negatively regulated by TGFβ/Smad3 signaling [195,196]. …”

Section: Trans-acting Regulators Of Htert Transcriptionmentioning

confidence: 99%

Transcription Regulation of the Human Telomerase Reverse Transcriptase (hTERT) Gene

Ramlee

Wang

Toh

et al. 2016

Genes

132

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Embryonic stem cells and induced pluripotent stem cells have the ability to maintain their telomere length via expression of an enzymatic complex called telomerase. Similarly, more than 85%–90% of cancer cells are found to upregulate the expression of telomerase, conferring them with the potential to proliferate indefinitely. Telomerase Reverse Transcriptase (TERT), the catalytic subunit of telomerase holoenzyme, is the rate-limiting factor in reconstituting telomerase activity in vivo. To date, the expression and function of the human Telomerase Reverse Transcriptase (hTERT) gene are known to be regulated at various molecular levels (including genetic, mRNA, protein and subcellular localization) by a number of diverse factors. Among these means of regulation, transcription modulation is the most important, as evident in its tight regulation in cancer cell survival as well as pluripotent stem cell maintenance and differentiation. Here, we discuss how hTERT gene transcription is regulated, mainly focusing on the contribution of trans-acting factors such as transcription factors and epigenetic modifiers, as well as genetic alterations in hTERT proximal promoter.

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Erythropoietin activates telomerase through transcriptional and posttranscriptional regulation in human erythroleukemic JAS-REN-A cells

Cited by 14 publications

References 7 publications

Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells

Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells

The role of the JAK-STAT pathway and related signal cascades in telomerase activation during the development of hematologic malignancies

Transcription Regulation of the Human Telomerase Reverse Transcriptase (hTERT) Gene

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