1,6-Diaminohexane contributes to the hexamethylene bisacetamide-induced erythroid differentiation pathway by stimulating Ca2+ release from inositol 1,4,5-trisphosphate-sensitive stores and promoting Ca2+ influx

Rajagopalan, Vanishree; Blankenship, J. W.; Thomas, David W.

doi:10.1016/j.abb.2005.11.003

Cited by 2 publications

(2 citation statements)

References 30 publications

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“…Because BAPTA-AM treatment completely inhibited type I IFN induction by HMBA, but inhibiting extracellular calcium alone (by nifedipine or EGTA) did not, our results suggest that the Ca 2+ influx is originating, at least in part, from the ER stores. This is in accordance with a study that reported HMBA triggers a release of calcium, in part from the inositol 1,4,5-trisphosphate-sensitive intracellular Ca 2+ stores (41).…”

Section: Discussionsupporting

confidence: 93%

Anti-Cancer Drug HMBA Acts as an Adjuvant during Intracellular Bacterial Infections by Inducing Type I IFN through STING

Gamage

Lee

Gan

2017

The Journal of Immunology

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The anti-proliferative agent hexamethylene bisacetamide (HMBA) belongs to a class of hybrid bipolar compounds developed more than 30 y ago for their ability to induce terminal differentiation of transformed cells. Recently, HMBA has also been shown to trigger HIV transcription from latently infected cells, via a CDK9/HMBA inducible protein-1 dependent process. However, the effect of HMBA on the immune response has not been explored. We observed that pretreatment of human peripheral blood mononuclear cells with HMBA led to a markedly increased production of IL-12 and IFN-γ, but not of TNF-α, IL-6, and IL-8 upon subsequent infection with and HMBA treatment was also associated with better intracellular bacterial control. HMBA significantly improved IL-12p70 production from CD14 monocytes during infection partly via the induction of type I IFN in these cells, which primed an increased transcription of the p35 subunit of IL-12p70 during infection. HMBA also increased early type I IFN transcription in human monocytic and epithelial cell lines, but this was surprisingly independent of its previously reported effects on positive transcription elongation factor b and HMBA inducible protein-1. Instead, the effect of HMBA was downstream of a calcium influx, and required the pattern recognition receptor and adaptor STING but not cGAS. Our work therefore links the STING-IRF3 axis to enhanced IL-12 production and intracellular bacterial control in primary monocytes. This raises the possibility that HMBA or related small molecules may be explored as therapeutic adjuvants to improve disease outcomes during intracellular bacterial infections.

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Section: Discussionsupporting

confidence: 93%

Anti-Cancer Drug HMBA Acts as an Adjuvant during Intracellular Bacterial Infections by Inducing Type I IFN through STING

Gamage

Lee

Gan

2017

The Journal of Immunology

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“…Alternatively, HMBA could mediate its effects on viral transcription via the activation of cellular kinases. Indeed, PKC and calcium pathways are activated by HMBA [18]. In addition, suberoylanilide hydroxamic acid (SAHA), a bipolar compound that is structurally similar to HMBA, activates Akt [19,20].…”

Section: Introductionmentioning

confidence: 99%

HMBA Releases P-TEFb from HEXIM1 and 7SK snRNA via PI3K/Akt and Activates HIV Transcription

et al. 2007

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Hexamethylene bisacetamide (HMBA) is a potent inducer of cell differentiation and HIV production in chronically infected cells. However, its mechanism of action remains poorly defined. In this study, we demonstrate that HMBA activates transiently the PI3K/Akt pathway, which leads to the phosphorylation of HEXIM1 and the subsequent release of active positive transcription elongation factor b (P-TEFb) from its transcriptionally inactive complex with HEXIM1 and 7SK small nuclear RNA (snRNA). As a result, P-TEFb is recruited to the HIV promoter to stimulate transcription elongation and viral production. Despite the continuous presence of HMBA, the released P-TEFb reassembles rapidly with 7SK snRNA and HEXIM1. In contrast, a mutant HEXIM1 protein that cannot be phosphorylated and released from P-TEFb and 7SK snRNA via the PI3K/Akt pathway antagonizes this HMBA-mediated induction of viral production. Thus, our studies reveal how HIV transcription is induced by HMBA and suggest how modifications in the equilibrium between active and inactive P-TEFb could contribute to cell differentiation.

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1,6-Diaminohexane contributes to the hexamethylene bisacetamide-induced erythroid differentiation pathway by stimulating Ca2+ release from inositol 1,4,5-trisphosphate-sensitive stores and promoting Ca2+ influx

Cited by 2 publications

References 30 publications

Anti-Cancer Drug HMBA Acts as an Adjuvant during Intracellular Bacterial Infections by Inducing Type I IFN through STING

Anti-Cancer Drug HMBA Acts as an Adjuvant during Intracellular Bacterial Infections by Inducing Type I IFN through STING

HMBA Releases P-TEFb from HEXIM1 and 7SK snRNA via PI3K/Akt and Activates HIV Transcription

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