The Heat Shock Protein 90-CDC37 Chaperone Complex Is Required for Signaling by Types I and II Interferons

Shang, Limin; Tomasi, Thomas B.

doi:10.1074/jbc.m509901200

Cited by 60 publications

(57 citation statements)

References 49 publications

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“…T-cell activation is initiated by the concomitant stimulation of both the T-cell receptor CD3 and the coreceptor CD28, and involves intermediates such as Raf-1, Akt, Jak, and STAT5, 8 which have previously been shown to be dependent on appropriate Hsp90 chaperone function in various mammalian cell types. [21][22][23][24][25][26] In this study, we could show that signaling through the Jak/STAT5, Ras/ERK1,2, and phosphatidylinositol 3-kinase/Akt signaling pathways, which are activated in T cells after combined stimulation with anti-CD3 and anti-CD28 beads, was indeed effectively abrogated by inhibition of Hsp90. Taken together, the interplay of signaling pathways and Hsp90-chaperoning activity facilitates function and survival of activated T cells, and pharmacologic targeting of Hsp90 activity might therefore be an effective attempt to induce cell death in activated T cells.…”

Section: Discussionmentioning

confidence: 63%

Selective depletion of alloreactive T cells by targeted therapy of heat shock protein 90: a novel strategy for control of graft-versus-host disease

Stuehler

Mielke

Chatterjee

et al. 2009

Blood

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Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients with hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation. Current treatment of GVHD relies on immunosuppressive regimens, considerably increasing the incidence of opportunistic infections. As T cells mediate both GVHD as well as protection against viral infections and the malignant disease, strategies to selectively target host-reactive T cells without impairing pathogen-and disease-specific immunity are highly warranted. Activation of T cells is accompanied by increased expression of the chaperone heat shock protein of 90 kDa (Hsp90), which stabilizes several key signaling pathways crucial for T-cell activation. In this study, selective targeting of Hsp90 in activated T lymphocytes with pharmacologic inhibitors already applied successfully in anticancer therapy resulted in induction of apoptosis predominantly in activated cells. Moreover, if T cells were stimulated with allogeneic dendritic cells, alloreactive T cells were selectively eliminated. In contrast, third party reactions including antiviral T-cell immunity were quantitatively and functionally fully preserved. These data suggest that Hsp90 represents a novel target for selective depletion of alloreactive T cells, and provide the rationale for application of Hsp90 inhibitors as potential approach to selectively prevent and treat GVHD in hematopoietic stem cell transplantation recipients without impairing pathogen-and disease-specific T-cell immunity. (Blood.

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Section: Discussionmentioning

confidence: 63%

Selective depletion of alloreactive T cells by targeted therapy of heat shock protein 90: a novel strategy for control of graft-versus-host disease

Stuehler

Mielke

Chatterjee

et al. 2009

Blood

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“…H186A mutation of CHORDC1 was shown to have a weaker nucleotide-dependent interaction with HSP90 compared with wild-type CHORDC1 (45). However, neither H186A mutation of CHORDC1 nor knockdown of HSP90 expression by siRNA (46) could efficiently attenuate the enhancement of HBV production by CHORDC1 (data not shown). Future studies are needed to answer this question.…”

Section: Discussionmentioning

confidence: 90%

MicroRNA-26b Inhibits Hepatitis B Virus Transcription and Replication by Targeting the Host Factor CHORDC1 Protein

Zhao¹,

Xu²,

Zhou³

et al. 2014

Journal of Biological Chemistry

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Background: Disordered miR-26b expression has been linked to the development of many diseases induced by hepatitis B virus (HBV). Results: miR-26b inhibits HBV replication, and HBV infection suppresses miR-26b expression. Conclusion: miR-26b acts as a host restriction factor to attenuate HBV transcription and replication. Significance: The functional interplay between HBV infection and miR-26b may influence the outcome of viral proliferation and virus-induced diseases.

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“…Indeed, ITF2357 is known to inhibit HDAC6, 19,33 the enzyme that regulates HSP90 acetylation [34][35][36] and JAK1/2 have recently been shown to be client proteins of HSP90. 37 Another possibility, given that HDACi have been demonstrated to hyperacetylate a number of proteins other than histones, The HDAC inhibitor ITF2357 downmodulates JAK2 V617F V Guerini et al including tubulin, p53 and BCL-6, 38,39 is that ITF2357 may induce hyperacetylation of JAK2 itself or of another protein involved in its stabilization, such as SOCS1. 8,40 All these different hypotheses are currently under investigation and are beyond the scope of this report.…”

Section: Discussionmentioning

confidence: 99%

The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2V617F

et al. 2007

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We investigated the activity of ITF2357, a novel histone deacetylase inhibitor (HDACi) with antitumor activity, on cells carrying the JAK2 V617F mutation obtained from polycythemia vera (PV) and essential thrombocythemia (ET) patients as well as the HEL cell line. The clonogenic activity of JAK2 V617F mutated cells was inhibited by low concentrations of ITF2357 (IC 50 0.001-0.01 lM), 100-to 250-fold lower than required to inhibit growth of normal or tumor cells lacking this mutation. Under these conditions, ITF2357 allowed a seven fold increase in the outgrowth of unmutated over mutated colonies. By western blotting we showed that in HEL cells, ITF2357 led to the disappearance of total and phosphorylated JAK2 V617F as well as pSTAT5 and pSTAT3, but it did not affect the wild-type JAK2 or STAT proteins in the control K562 cell line. By real-time PCR, we showed that, upon exposure to ITF2357, JAK2 V617F mRNA was not modified in granulocytes from PV patients while the expression of the PRV-1 gene, a known target of JAK2, was rapidly downmodulated. Altogether, the data presented suggest that ITF2357 inhibits proliferation of cells bearing the JAK2 V617F mutation through a specific downmodulation of the JAK2 V617F protein and inhibition of its downstream signaling.

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The Heat Shock Protein 90-CDC37 Chaperone Complex Is Required for Signaling by Types I and II Interferons

Cited by 60 publications

References 49 publications

Selective depletion of alloreactive T cells by targeted therapy of heat shock protein 90: a novel strategy for control of graft-versus-host disease

Selective depletion of alloreactive T cells by targeted therapy of heat shock protein 90: a novel strategy for control of graft-versus-host disease

MicroRNA-26b Inhibits Hepatitis B Virus Transcription and Replication by Targeting the Host Factor CHORDC1 Protein

The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2V617F

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