Cytosolic Hsp90 Isoform-Specific Functions and Clinical Significance

Maiti, Soumen; Picard, Didier

doi:10.3390/biom12091166

Cited by 39 publications

(13 citation statements)

References 189 publications

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“…We synthesized [ [20]. Although we did not con rm this ligand's a nity for other HSP90 isoforms in this study, other studies suggested that this ligand does not have any signi cant a nity for other HSP90 isoforms [17].…”

Section: Radiosynthesismentioning

confidence: 55%

A novel PET probe to selectively image heat shock protein 90α/β isoforms in the brain

Sakai,

Ikenuma,

Yamada

et al. 2023

Preprint

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Background Heat shock proteins (HSPs), ubiquitously found proteins called molecular chaperones in the brain, play important functional roles in the neuropathological processes of Alzheimer’s disease and Lewy body disease. Of many HSP subtypes, HSP90 has been shown to play a central role in the process. Many studies have shown that drugs that inhibit HSP90 activity have beneficial effects in the neurodegenerative diseases. Therefore, HSP90 PET imaging ligand, an in vivo biomarker of HSP90, can be used effectively to study HSP90 in neurodegenerative diseases. Among four HSP90 isoforms, two cytosolic isoforms (HSP90α and HSP90β) thought to be involved in the structural homeostasis of the proteins related to the neurodegenerative diseases. Currently, no useful PET imaging ligands selectively targeting the two cytosolic isoforms of HSP90 have been available yet. Results In this study, we developed a novel PET imaging ligand, [11C]NCGG801, selectively targeting HSP90α and HSP90β by radiolabeling BIIB021, an inhibitor with a high affinity for and selectivity to HSP90α and HSP90β. [11C]NCGG801 was synthesized with a high yield, molar activity and radiochemical purity. [11C]NCGG801 showed a high binding affinity for rat brain homogenate as well as human recombinant HSP90α and HSP90β proteins. This radioligand was well taken up into the rat brain (SUV 1.4) and showed clear specific binding in PET imaging of healthy rats and autoradiography of healthy rat and human brain sections. Conclusions Our data suggested that [11C]NCGG801 has a potential to be a new imaging biomarker of HSP90α/β in the brain. Further studies appear warranted to evaluate [11C]NCGG801 in humans.

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Section: Radiosynthesismentioning

confidence: 55%

A novel PET probe to selectively image heat shock protein 90α/β isoforms in the brain

Sakai,

Ikenuma,

Yamada

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…The lack of specificity in these inhibitors, largely due to the sequence identity among the four HSP90 isoforms, particularly the 85% similarity between HSP90α and HSP90β, remains a significant limitation. 9,279 Therefore, it is important to continue research on isoform-selective inhibitors, with the aim of mitigating generalized HSP90 inhibition. For instance, Mishra et al 280,281 analyzed differences between Hsp90α and Hsp90β in the ATP binding site, then used fluorescence assays to create highly selective inhibitors for Hsp90α and Hsp90β without raising Hsp90 levels, a significant advance in isoform-selective inhibitors.…”

Section: Conclusion and Prospectsmentioning

confidence: 99%

“…As of now, only one HSP90 inhibitor, pimitespib, has gained approval in Japan for GIST treatment. The lack of specificity in these inhibitors, largely due to the sequence identity among the four HSP90 isoforms, particularly the 85% similarity between HSP90α and HSP90β, remains a significant limitation 9,279 . Therefore, it is important to continue research on isoform‐selective inhibitors, with the aim of mitigating generalized HSP90 inhibition.…”

Section: Conclusion and Prospectsmentioning

confidence: 99%

Heat shock protein 90: biological functions, diseases, and therapeutic targets

Wei,

Zhang,

Jia

et al. 2024

MedComm

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Heat shock protein 90 (Hsp90) is a predominant member among Heat shock proteins (HSPs), playing a central role in cellular protection and maintenance by aiding in the folding, stabilization, and modification of diverse protein substrates. It collaborates with various co‐chaperones to manage ATPase‐driven conformational changes in its dimer during client protein processing. Hsp90 is critical in cellular function, supporting the proper operation of numerous proteins, many of which are linked to diseases such as cancer, Alzheimer's, neurodegenerative conditions, and infectious diseases. Recognizing the significance of these client proteins across diverse diseases, there is a growing interest in targeting Hsp90 and its co‐chaperones for potential therapeutic strategies. This review described biological background of HSPs and the structural characteristics of HSP90. Additionally, it discusses the regulatory role of heat shock factor‐1 (HSF‐1) in modulating HSP90 and sheds light on the dynamic chaperone cycle of HSP90. Furthermore, the review discusses the specific contributions of HSP90 in various disease contexts, especially in cancer. It also summarizes HSP90 inhibitors for cancer treatment, offering a thoughtful analysis of their strengths and limitations. These advancements in research expand our understanding of HSP90 and open up new avenues for considering HSP90 as a promising target for therapeutic intervention in a range of diseases.

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“…In mammalian cells, HSP90 exists in two paralogs, HSP90α and HSP90β 39 , both of which have been reported to play roles in epichaperome formation in cancer cells 13 . To assess the isoform composition of HSP90 within epichaperomes, we exploited the subtle difference between one pair of isobaric peptides, namely 88Thr-Lys100 in HSP90α and 83Thr-Lys95 in HSP90β, where a single amino acid distinguishes them (Ile in HSP90α and Leu in HSP90β) (Supplementary Fig.…”

Section: Pluripotent Stem Cells and Cancer Cells Share Epichaperomesmentioning

confidence: 99%

Phosphorylation-Driven Epichaperome Assembly: A Critical Regulator of Cellular Adaptability and Proliferation

Chiosis,

McNutt,

Roychowdhury

et al. 2024

Preprint

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The intricate protein-chaperone network is vital for cellular function. Recent discoveries have unveiled the existence of specialized chaperone complexes called epichaperomes, protein assemblies orchestrating the reconfiguration of protein-protein interaction networks, enhancing cellular adaptability and proliferation. This study delves into the structural and regulatory aspects of epichaperomes, with a particular emphasis on the significance of post-translational modifications in shaping their formation and function. A central finding of this investigation is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 situated within an intrinsically disordered region, as critical determinants in epichaperome assembly. Our data demonstrate that the phosphorylation of these serine residues enhances HSP90's interaction with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Furthermore, this study establishes a direct link between epichaperome function and cellular physiology, especially in contexts where robust proliferation and adaptive behavior are essential, such as cancer and stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone complexes in diseases characterized by epichaperome dysregulation, bridging the gap between fundamental research and precision medicine.

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Cytosolic Hsp90 Isoform-Specific Functions and Clinical Significance

Cited by 39 publications

References 189 publications

A novel PET probe to selectively image heat shock protein 90α/β isoforms in the brain

A novel PET probe to selectively image heat shock protein 90α/β isoforms in the brain

Heat shock protein 90: biological functions, diseases, and therapeutic targets

Phosphorylation-Driven Epichaperome Assembly: A Critical Regulator of Cellular Adaptability and Proliferation

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