The remarkable multivalency of the Hsp70 chaperones

Zuiderweg, Erik R. P.; Hightower, Lawrence E.; Gestwicki, Jason E.

doi:10.1007/s12192-017-0776-y

Cited by 112 publications

(119 citation statements)

References 90 publications

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“…HSP72 and HSP73 promote tumor cell survival in MM by contributing to the chaperone function of HSP90 . Inhibition of these proteins induces apoptosis, further highlighting the important role of HSP70 proteins in the biology of MM and ER stress management . Their relative upregulation in MM and known role in modulating ER stress has led to the development of a number of therapies targeting these proteins (see below for more detail).…”

Section: Modulation Of Er Stress In MMmentioning

confidence: 99%

“…48 Inhibition of these proteins induces apoptosis, further highlighting the important role of HSP70 proteins in the biology of MM and ER stress management. 44,48 Their relative upregulation in MM and known role in modulating ER stress has led to the development of a number of therapies targeting these proteins (see below for more detail). Furthermore, the glucose-regulated protein 94 (GRP94) (also known as HSP90B1) protein plays a significant role in ER protein quality control, via protein folding capabilities, and also serves an equally important role in orchestrating ERAD.…”

Section: Modulation Of Er Stress In MMmentioning

confidence: 99%

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Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance

et al. 2018

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Multiple myeloma (MM) is a haematological malignancy of mature antibody‐secreting plasma cells. Currently, MM is incurable, but advances in drug treatments have increased patient lifespan. One of the characteristics of MM is the excessive production of monoclonal immunoglobulin (also referred to as paraprotein). This high level of protein production induces endoplasmic reticulum (ER) stress, and proteasomal degradation of the paraprotein is required to avoid ER stress‐induced cell death. Consequently, proteasomal inhibitors such as bortezomib have been particularly effective therapies. Unfortunately development of resistance to bortezomib is common. In this review, we address how control of endoplasmic reticulum stress is important in the development of MM and how the unfolded protein response and its associated stress response pathways are involved in the development of bortezomib resistance.

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Section: Modulation Of Er Stress In MMmentioning

confidence: 99%

Section: Modulation Of Er Stress In MMmentioning

confidence: 99%

Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance

et al. 2018

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“…HSP70 proteins have dynamic structures with nucleotide and substrate binding domains undergoing dramatic conformational changes upon nucleotide or substrate binding 27,28 . As R469 resides in the substrate binding domain, we examined the 3D protein structure to determine the accessibility of the R469 side chain.…”

Section: Prmt7 Methylation Of Hsp70 In Vitro Reveals a Dependency On mentioning

confidence: 99%

Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress responses

Szewczyk

Ishikawa

Organ

et al. 2018

Preprint

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AbstractProtein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. Here we report the discovery of a potent, selective and cell active chemical probe for PRMT7. SGC3027 is a cell permeable prodrug, which in cells, is converted to SGC8158, a potent, SAM-competitive PRMT7 inhibitor. Inhibition or knockout of cellular PRMT7 resulted in drastically reduced levels of arginine monomethylation of HSP70 family members and other stress-associated proteins. Structural and biochemical analysis revealed that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibited methylation of both constitutive and inducible forms of HSP70, and led to decreased tolerance for perturbations of proteostasis including heat shock and proteasome inhibitors. These results demonstrate a role for PRMT7 and arginine methylation in stress response.

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“…Fungi can also respond to temperature fluctuations through the induction of a diverse set of heat shock proteins. These include the small heat shock proteins, which can shift from a low to high-affinity chaperone state upon heat stress [21,22], Hsp70 proteins, which are required for maintaining protein homeostasis [23], and the molecular chaperone Hsp90. Hsp90 is a highly conserved ATP-dependent molecular chaperone that acts to stabilize components of signal transduction cascades, especially those involved in adaptation to stress [24-26].…”

Section: Hsp90 Enables Temperature-dependent Morphogenesis Drug Resimentioning

confidence: 99%

The Hsp90 Chaperone Network Modulates Candida Virulence Traits

O’Meara

Robbins

Cowen

2017

Trends in Microbiology

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Hsp90 is a conserved molecular chaperone that facilitates the folding and function of client proteins. Hsp90 function is dynamically regulated by interactions with co-chaperones and by post-translational modifications. In the fungal pathogen Candida albicans, Hsp90 enables drug resistance and virulence by stabilizing diverse signal transducers. Here, we review studies that have unveiled regulators of Hsp90 function, as well as downstream effectors that govern the key virulence traits of morphogenesis and drug resistance. We highlight recent work mapping the Hsp90 genetic network in C. albicans under diverse environmental conditions, and how these interactions provide insight into circuitry important for drug resistance, morphogenesis, and virulence. Ultimately, elucidating the Hsp90 chaperone network will aid in the development of therapeutics to treat fungal disease.

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The remarkable multivalency of the Hsp70 chaperones

Cited by 112 publications

References 90 publications

Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance

Endoplasmic reticulum stress in the development of multiple myeloma and drug resistance

Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress responses

The Hsp90 Chaperone Network Modulates Candida Virulence Traits

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