HSP27 is a partner of JAK2-STAT5 and a potential therapeutic target in myelofibrosis

Sevin, Margaux; Kubovčáková, Lucia; Pernet, Nicolas; Causse, Sébastien; Vitte, Franck; Villeval, Jean‐Luc; Lacout, Catherine; Cordonnier, Marine; Rodrigues‐Lima, Fernando; Chanteloup, Gaëtan; Mosca, Matthieu; Chrétien, Marie‐Lorraine; Bastié, Jean; Audia, Sylvain; Sagot, Paul; Ramla, Selim; Martin, Laurent; Gleave, Martin; Mezger, Valérie; Skoda, Radek C.; Plo, Isabelle; Garrido, Carmen; Girodon, François; Thonel, Aurélie de

doi:10.1038/s41467-018-03627-9

Cited by 20 publications

(20 citation statements)

References 75 publications

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“…Besides recognizing pathogens, TLR2 and TLR4 can also be stimulated by diverse endogenous ligands and thereby participate in thromboinflammatory reactions that take place in clinical conditions characterized by sterile inflammation, thus contributing to vascular disease (25). Previous findings from our group and others have revealed the presence of host-derived TLR ligands in MPN, including histone/DNA complexes (26), Hsp27 (27) and EDA-fibronectin (28), which engage TLR2 and/or TLR4. In order to determine the potential contribution of TLRs to platelet activation in ET, we assessed TLR2-and TLR4-mediated platelet thromboinflammatory responses, using the synthetic lipopeptide Pam3CSK4 and LPS, as prototypical TLR2/1 and TLR4 ligands, respectively, and employed classic hemostatic agonists, such as TRAP-6 and thrombin, for comparison.…”

Section: Introductionmentioning

confidence: 93%

Platelet Toll-Like Receptors Mediate Thromboinflammatory Responses in Patients With Essential Thrombocythemia

et al. 2020

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Platelet Toll-Like Receptors in Essential Thrombocythemia downstream effector ERK1/2 was higher in patients at baseline and after incubation with Pam3CSK4, which may partly explain the enhanced TLR2 response. In conclusion, exacerbated response to TLR stimulation may promote platelet activation in ET, boosting platelet/leukocyte/endothelial interactions and secretion of inflammatory mediators, overall reinforcing the thromboinflammatory state. These findings highlight the role of platelets as inflammatory sentinels in MPN prothrombotic scenario and provide additional evidence for the close intertwining between thrombosis and inflammation in this setting.

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Section: Introductionmentioning

confidence: 93%

Platelet Toll-Like Receptors Mediate Thromboinflammatory Responses in Patients With Essential Thrombocythemia

et al. 2020

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“…Upstream from STAT3/5 activation, JAK2 plays a major role that can be modulated by HSP27 [141]. In the specific context of thrombopoietin-and JAK2 V617F -induced myelofibrosis (a chronic degenerative disorder of the hematopoietic system associated with the aberrant activation of the JAK/STAT pathway) [142], our team has recently shown that HSP27 interacts directly with JAK2/STAT5, stabilizing the complex.…”

Section: Hsp27 Functionsmentioning

confidence: 99%

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

Hermetet

Girodon

Jego

2019

Cancers

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While cells from multicellular organisms are dependent upon exogenous signals for their survival, growth, and proliferation, commitment to a specific cell fate requires the correct folding and maturation of proteins, as well as the degradation of misfolded or aggregated proteins within the cell. This general control of protein quality involves the expression and the activity of molecular chaperones such as heat shock proteins (HSPs). HSPs, through their interaction with the STAT3/STAT5 transcription factor pathway, can be crucial both for the tumorigenic properties of cancer cells (cell proliferation, survival) and for the microenvironmental immune cell compartment (differentiation, activation, cytokine secretion) that contributes to immunosuppression, which, in turn, potentially promotes tumor progression. Understanding the contribution of chaperones such as HSP27, HSP70, HSP90, and HSP110 to the STAT3/5 signaling pathway has raised the possibility of targeting such HSPs to specifically restrain STAT3/5 oncogenic functions. In this review, we present how HSPs control STAT3 and STAT5 activation, and vice versa, how the STAT signaling pathways modulate HSP expression. We also discuss whether targeting HSPs is a valid therapeutic option and which HSP would be the best candidate for such a strategy.

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“…Nucleic acids. Built from a selection of four natural building blocks (G, C, A, T/U) and additional artificial ones, DNA/RNA sequences operate either by interfering with gene expression, e.g., antisense oligonucleotides [50][51][52] and RNAi [53][54][55] , or through their unique folding geometry, which allows them to interact structurally with a target molecule, e.g., aptamers 41,56-60 and ribozymes [61][62][63] . While not widespread at this point, these short DNA-sequences have already proven their potential efficacy, for example inhibiting the activity of human immunodeficiency virus (HIV) 64,65 , as well as other applications at various stages of clinical trials 58 .…”

Section: Box I Digitizable Therapeuticsmentioning

confidence: 99%

Digital therapeutics for distributed response to global pandemics

Hacohen¹,

Cohen

Efroni

et al. 2018

Preprint

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Despite advances in the development of drugs and vaccines, the spread of infectious diseases remains an imminent threat to our global health, in extreme cases potentially having detrimental consequences. At present our response to this threat is based on physically distributing therapeutic material, which utilizes the same transportation networks that support the spread of the infectious agent itself. Such competition is at risk of failure in the face of a rapidly spreading pathogen, especially given the inevitable delay from the initial outbreak to the development and execution of our response. Moreover, based on our existing transportation networks, we show that such physical distribution is intrinsically inefficient, leading to an uneven concentration of the therapeutic within a small fraction of destinations, while leaving the majority of the population deprived. This suggests that outrunning a virulent epidemic can only be achieved if we develop a mitigation strategy that bypasses the existing distribution networks of biological and chemical material. Here we propose such a response, utilizing digitizable therapeutics, which can be distributed as digital sequence files and synthesized on location, exposing an extremely efficient mitigation scheme that systematically outperforms physical distribution. Our proposed strategy, based for example on nucleic acid therapeutics, is plausibly the only viable mitigation plan, based on current technology, that can face a violently spreading pathogen. Complementing the current paradigm, which ranks drugs based on efficacy, our analysis demonstrates the importance of balancing efficacy with distributability, finding that in some cases the latter plays the dominant role in the overall mitigation efficiency.When studied from the angle of its worst-case scenario, surviving a highly infectious pandemic depends on a competition between the infectious pathogen and the therapeutic technology, each racing to reach the majority of the population first. This competition confronts us with several challenges: (i) the inevitable response time R required for us to instigate a mitigation plan places the pathogen at a potentially significant spreading advantage; (ii) while the pathogen reproduces as it spreads 1-3 , a therapy must be manufactured and shipped from one or few sources, whose production and distribution capacity may be limited 4-12 ; (iii) the dissemination of antibiotics or vaccines can be hindered by various external factors, such as geopolitical and socio-economical constraints [13][14][15][16] , which have little effect on the propagation of bacteria and viruses. But even if such factors are eliminated, e.g., assuming that an effective cure already exists, stockpiled in sufficient quantities and benefits from worldwide cooperation in its distribution, it would still have to outrun the pathogen, competing along the same routes of dissemination as the epidemic, i.e. the international transportation networks 17-23 . For a rapidly progressing epidemic, such competition may f...

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HSP27 is a partner of JAK2-STAT5 and a potential therapeutic target in myelofibrosis

Cited by 20 publications

References 75 publications

Platelet Toll-Like Receptors Mediate Thromboinflammatory Responses in Patients With Essential Thrombocythemia

Platelet Toll-Like Receptors Mediate Thromboinflammatory Responses in Patients With Essential Thrombocythemia

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

Digital therapeutics for distributed response to global pandemics

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