Heat Shock Protein 90 Regulates Subcellular Localization of Smads in Mv1Lu Cells

Lee, Jeeyong; An, You Sun; Kim, Mi-Ra; Kim, Ye-Ah; Lee, Jin Kyung; Hwang, Chang Sun; Chung, Eun-Kyung; Park, In-Chul; Yi, Jianxun

doi:10.1002/jcb.25269

Cited by 14 publications

(12 citation statements)

References 25 publications

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“…TGF-β intracellular signaling represents a complex network that involves several kinases classified in two main cascades: Smad- and non-Smad-dependent [ 36 ]. HSP90 is involved in both as many of its client proteins belong to the non-Smad dependent pathway and, at the same time, HSP90 is able to modulate Smad localization [ 37 ]. The HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17AAG), attenuates renal fibrosis through inhibition of Smad phosphorylation [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

The HSP90 Inhibitor, AUY-922, Ameliorates the Development of Nitrogen Mustard-Induced Pulmonary Fibrosis and Lung Dysfunction in Mice

Solopov

Biancatelli

Маринова

et al. 2020

IJMS

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Increased levels of heat shock protein 90 (HSP90) have been recently implicated in the pathogenesis of pulmonary fibrosis and the use of HSP90 inhibitors constitutes a potential therapeutic approach. Similarly, acute exposure to nitrogen mustard (NM) is related to the development of chronic lung injury driven by TNF-α, TGF-β, ERK and HSP90. Thus, we developed a murine model of NM-induced pulmonary fibrosis by instilling C57BI/6J mice with 0.625 mg/kg mechlorethamine hydrochloride. After 24 h, mice began receiving AUY-922, a second generation HSP90 inhibitor, at 1 mg/kg 2 times per week or 2 mg/kg 3 times per week, for either 10 or 30 days. AUY-922 suppressed the NM-induced sustained inflammation, as reflected in the reduction of leukocyte and protein concentrations in bronchoalveolar lavage fluid (BALF), and inhibited the activation of pro-fibrotic biomarkers, ERK and HSP90. Furthermore, AUY-922 maintained normal lung function, decreased the overexpression and accumulation of extracellular matrix proteins, and dramatically reduced histologic evidence of fibrosis in the lungs of mice exposed to NM. The HSP90 inhibitor, AUY-922, successfully blocked the adverse effects associated with acute exposures to NM, representing a promising approach against NM-induced pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

The HSP90 Inhibitor, AUY-922, Ameliorates the Development of Nitrogen Mustard-Induced Pulmonary Fibrosis and Lung Dysfunction in Mice

Solopov

Biancatelli

Маринова

et al. 2020

IJMS

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“…Furthermore, HSP90 plays a critical role in TGFβ function by stabilizing its signaling cascade and receptors [63,72]. At the same time HSP90 regulates nuclear localization of Smad, influencing and modulating the Smad-dependent signaling cascade of TGF-β [73]. TGF-β, the leading cytokine in IPF, is responsible for the epithelial-to-mesenchymal transformation (EMT) of epithelial cells into a myofibroblastic phenotype that is related to the transformation of lung structure and the production of extracellular matrix (ECM) [74], thus, interference with its complex signaling cascade represents a reasonable therapeutic approach for IPF, supported by a strong mechanistic rationale.…”

Section: Hsp90 Pathways In Pulmonary Fibrosismentioning

confidence: 99%

HSP90 Inhibition and Modulation of the Proteome: Therapeutical Implications for Idiopathic Pulmonary Fibrosis (IPF)

Biancatelli

Solopov

Gregory

et al. 2020

IJMS

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Idiopathic Pulmonary fibrosis (IPF) is a catastrophic disease with poor outcomes and limited pharmacological approaches. Heat shock protein 90 (HSP90) has been recently involved in the wound-healing pathological response that leads to collagen deposition in patients with IPF and its inhibition represents an exciting drug target against the development of pulmonary fibrosis. Under physiological conditions, HSP90 guarantees proteostasis through the refolding of damaged proteins and the degradation of irreversibly damaged ones. Additionally, its inhibition, by specific HSP90 inhibitors (e.g., 17 AAG, 17 DAG, and AUY-922) has proven beneficial in different preclinical models of human disease. HSP90 inhibition modulates a complex subset of kinases and interferes with intracellular signaling pathways and proteome regulation. In this review, we evaluated the current evidence and rationale for the use of HSP90 inhibitors in the treatment of pulmonary fibrosis, discussed the intracellular pathways involved, described the limitations of the current understanding and provided insights for future research.

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“…Targeting protein subcellular localization is considered challenging, because the protein may be transported out of the nucleus after being induced into the nucleus [ 41 ]. The Bcr-Abl and c-Abl have similar structural sites, both containing three nuclear localization signals and a nuclear output signal, so it can shuttle between the cytoplasm and nucleus, but is mainly located in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Effect of HSP90AB1 and CC domain interaction on Bcr-Abl protein cytoplasm localization and function in chronic myeloid leukemia cells

et al. 2021

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Background The fusion oncoprotein Bcr-Abl is mostly located in the cytoplasm, which causes chronic myeloid leukemia (CML). After moving into the nucleus, the fusion protein can induce apoptosis of CML cells. The coiled-coil domain (CC domain) of Bcr-Abl protein plays a central role in the subcellular localization. However, how CC domain affects subcellular localization of Bcr-Abl remains unclear. Methods Herein, the key proteins interacting with the Bcr-Abl CC domain were screened by immunoprecipitation binding mass spectrometry. The specific site of Bcr-Abl CC domain binding to target protein was predicted by Deep Viewer. Immunoprecipitation assay was used to confirmed the specific sites of protein binding. IF and western blot were used to observe the subcellular localization of target protein. Western blot was used to examine the protein changes. CCK-8, clonal formation test and FCM cycle detection were used to observe the effect of inhibitor on the proliferation ability of CML cells. FCM apoptosis detection was used to observe the level of cells apoptosis. Results HSP90AB1 interacts with Bcr-Abl CC domain via N-terminal domain (NTD), preventing the transport of Bcr-Abl protein to the nucleus and maintaining the activation of Bcr-Abl tyrosine kinase. The nucleus-entrapped Bcr-Abl markedly inhibits the proliferation and induces apoptosis of CML cells by activating p73 and repressing the expression of cytoplasmic oncogenic signaling pathways mediated by Bcr-Abl. Moreover, the combination of 17AAG (Tanespimycin) with Leptomycin B (LMB) considerably decreased the proliferation of CML cells. Conclusion Our study provides evidence that it is feasible to transport Bcr-Abl into the nucleus as an alternative strategy for the treatment of CML, and targeting the NTD of HSP90AB1 to inhibit the interaction with Bcr-Abl is more accurate for the development and application of HSP90 inhibitor in the treatment of CML and other Bcr-Abl-addicted malignancies.

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Heat Shock Protein 90 Regulates Subcellular Localization of Smads in Mv1Lu Cells

Cited by 14 publications

References 25 publications

The HSP90 Inhibitor, AUY-922, Ameliorates the Development of Nitrogen Mustard-Induced Pulmonary Fibrosis and Lung Dysfunction in Mice

The HSP90 Inhibitor, AUY-922, Ameliorates the Development of Nitrogen Mustard-Induced Pulmonary Fibrosis and Lung Dysfunction in Mice

HSP90 Inhibition and Modulation of the Proteome: Therapeutical Implications for Idiopathic Pulmonary Fibrosis (IPF)

Effect of HSP90AB1 and CC domain interaction on Bcr-Abl protein cytoplasm localization and function in chronic myeloid leukemia cells

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